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Research shows working out gets inflammation-fighting t cells moving.

Ekaterina Pesheva

HMS Communications

Activated by regular exercise, immune cells in muscles found to fend off inflammation, enhance endurance in mice

The connection between exercise and inflammation has captivated the imagination of researchers ever since an  early 20th-century study  showed a spike of white cells in the blood of Boston marathon runners following the race.

Now, a new Harvard Medical School study published Friday in Science Immunology may offer a molecular explanation behind this century-old observation.

The study, done in mice, suggests that the beneficial effects of exercise may be driven, at least partly, by the immune system. It shows that muscle inflammation caused by exertion mobilizes inflammation-countering T cells, or Tregs, which enhance the muscles’ ability to use energy as fuel and improve overall exercise endurance.

Long known for their role in countering the aberrant inflammation linked to autoimmune diseases, Tregs now also emerge as key players in the body’s immune responses during exercise, the research team said.

“The immune system, and the T cell arm in particular, has a broad impact on tissue health that goes beyond protection against pathogens and controlling cancer. Our study demonstrates that the immune system exerts powerful effects inside the muscle during exercise,” said study senior investigator  Diane Mathis , professor of immunology in the Blavatnik Institute at HMS.

Mice are not people, and the findings remain to be replicated in further studies, the researchers cautioned. However, the study is an important step toward detailing the cellular and molecular changes that occur during exercise and confer health benefits.

Understanding the molecular underpinnings of exercise

Protecting from cardiovascular disease, reducing the risk of diabetes, shielding against dementia. The salutary effects of exercise are well established. But exactly how does exercise make us healthy? The question has intrigued researchers for a long time.

The new findings come amid  intensifying efforts  to understand the molecular underpinnings of exercises. Untangling the immune system’s involvement in this process is but one aspect of these research efforts.

“Our research suggests that with exercise, we have a natural way to boost the body’s immune responses to reduce inflammation.” Diane Mathis, professor of immunology in the Blavatnik Institute

“We’ve known for a long time that physical exertion causes inflammation, but we don’t fully understand the immune processes involved,” said study first author Kent Langston, a postdoctoral researcher in the Mathis lab. “Our study shows, at very high resolution, what T cells do at the site where exercise occurs, in the muscle.”

Most previous research on exercise physiology has focused on the role of various hormones released during exercise and their effects on different organs such as the heart and the lungs. The new study unravels the immunological cascade that unfolds inside the actual site of exertion — the muscle.

T cell heroes and inflammation-fueling villains

Exercise is known to cause temporary damage to the muscles, unleashing a cascade of inflammatory responses. It boosts the expression of genes that regulate muscle structure, metabolism, and the activity of mitochondria, the tiny powerhouses that fuel cell function. Mitochondria play a key role in exercise adaptation by helping cells meet the greater energy demand of exercise.

In the new study, the team analyzed what happens in cells taken from the hind leg muscles of mice that ran on a treadmill once and animals that ran regularly. Then, the researchers compared them with muscle cells obtained from sedentary mice.

The muscle cells of the mice that ran on treadmills, whether once or regularly, showed classic signs of inflammation — greater activity in genes that regulate various metabolic processes and higher levels of chemicals that promote inflammation, including interferon.

Both groups had elevated levels of Treg cells in their muscles. Further analyses showed that in both groups, Tregs lowered exercise-induced inflammation. None of those changes were seen in the muscle cells of sedentary mice.

However, the metabolic and performance benefits of exercise were apparent only in the regular exercisers — the mice that had repeated bouts of running. In that group, Tregs not only subdued exertion-induced inflammation and muscle damage, but also altered muscle metabolism and muscle performance, the experiments showed. This finding aligns with well-established observations in humans that a single bout of exercise does not lead to significant improvements in performance and that regular activity over time is needed to yield benefits.

The hind leg muscles of mice lacking Treg cells (right) showed prominent signs of inflammation after regular exercise, compared with those from mice with intact Tregs (left). The research showed such that this uncontrolled inflammation negatively impacted muscle metabolism and function.

Credit: Kent Langston/Mathis Lab, HMS

Further analyses confirmed that Tregs were, indeed, responsible for the broader benefits seen in regular exercisers. Animals that lacked Tregs had unrestrained muscle inflammation, marked by the rapid accumulation of inflammation-promoting cells in their hind leg muscles. Their muscle cells also had strikingly swollen mitochondria, a sign of metabolic abnormality.

More importantly, animals lacking Tregs did not adapt to increasing demands of exercise over time the way mice with intact Tregs did. They did not derive the same whole-body benefits from exercise and had diminished aerobic fitness.

These animals’ muscles also had excessive amounts of interferon, a known driver of inflammation. Further analyses revealed that interferon acts directly on muscle fibers to alter mitochondrial function and limit energy production. Blocking interferon prevented metabolic abnormalities and improved aerobic fitness in mice lacking Tregs.

“The villain here is interferon,” Langston said. “In the absence of guardian Tregs to counter it, interferon went on to cause uncontrolled damage.”

Interferon is known to promote chronic inflammation, a process that underlies many chronic diseases and age-related conditions and has become a tantalizing target for therapies aimed at reducing inflammation. Tregs have also captured the attention of scientists and industry as treatments for a range of immunologic conditions marked by abnormal inflammation.

The study findings provide a glimpse into the cellular innerworkings behind exercise’s anti-inflammatory effects and underscore its importance in harnessing the body’s own immune defenses, the researchers said.

There are efforts afoot to design interventions targeting Tregs in the context of specific immune-mediated diseases. And while immunologic conditions driven by aberrant inflammation require carefully calibrated therapies, exercise is yet another way to counter inflammation, the researchers said.

“Our research suggests that with exercise, we have a natural way to boost the body’s immune responses to reduce inflammation,” Mathis said. “We’ve only looked in the muscle, but it’s possible that exercise is boosting Treg activity elsewhere in the body as well.”

Co-investigators included Yizhi Sun, Birgitta Ryback, Bruce Spiegelman, Amber Mueller, and Christophe Benoist.

The work was funded by National Institutes of Health grants R01 AR070334, F32 AG072874, and F32 AG069363; and by the JPB Foundation.

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• Research article
• Open access
• Published: 16 November 2020

Exercise/physical activity and health outcomes: an overview of Cochrane systematic reviews

• Pawel Posadzki 1 , 2 ,
• Dawid Pieper   ORCID: orcid.org/0000-0002-0715-5182 3 ,
• Ram Bajpai 4 ,
• Hubert Makaruk 5 ,
• Nadja Könsgen 3 ,
• Annika Lena Neuhaus 3 &
• Monika Semwal 6  

BMC Public Health volume  20 , Article number:  1724 ( 2020 ) Cite this article

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Sedentary lifestyle is a major risk factor for noncommunicable diseases such as cardiovascular diseases, cancer and diabetes. It has been estimated that approximately 3.2 million deaths each year are attributable to insufficient levels of physical activity. We evaluated the available evidence from Cochrane systematic reviews (CSRs) on the effectiveness of exercise/physical activity for various health outcomes.

Overview and meta-analysis. The Cochrane Library was searched from 01.01.2000 to issue 1, 2019. No language restrictions were imposed. Only CSRs of randomised controlled trials (RCTs) were included. Both healthy individuals, those at risk of a disease, and medically compromised patients of any age and gender were eligible. We evaluated any type of exercise or physical activity interventions; against any types of controls; and measuring any type of health-related outcome measures. The AMSTAR-2 tool for assessing the methodological quality of the included studies was utilised.

Hundred and fifty CSRs met the inclusion criteria. There were 54 different conditions. Majority of CSRs were of high methodological quality. Hundred and thirty CSRs employed meta-analytic techniques and 20 did not. Limitations for studies were the most common reasons for downgrading the quality of the evidence. Based on 10 CSRs and 187 RCTs with 27,671 participants, there was a 13% reduction in mortality rates risk ratio (RR) 0.87 [95% confidence intervals (CI) 0.78 to 0.96]; I 2  = 26.6%, [prediction interval (PI) 0.70, 1.07], median effect size (MES) = 0.93 [interquartile range (IQR) 0.81, 1.00]. Data from 15 CSRs and 408 RCTs with 32,984 participants showed a small improvement in quality of life (QOL) standardised mean difference (SMD) 0.18 [95% CI 0.08, 0.28]; I 2  = 74.3%; PI -0.18, 0.53], MES = 0.20 [IQR 0.07, 0.39]. Subgroup analyses by the type of condition showed that the magnitude of effect size was the largest among patients with mental health conditions.

There is a plethora of CSRs evaluating the effectiveness of physical activity/exercise. The evidence suggests that physical activity/exercise reduces mortality rates and improves QOL with minimal or no safety concerns.

Trial registration

Registered in PROSPERO ( CRD42019120295 ) on 10th January 2019.

Peer Review reports

The World Health Organization (WHO) defines physical activity “as any bodily movement produced by skeletal muscles that requires energy expenditure” [ 1 ]. Therefore, physical activity is not only limited to sports but also includes walking, running, swimming, gymnastics, dance, ball games, and martial arts, for example. In the last years, several organizations have published or updated their guidelines on physical activity. For example, the Physical Activity Guidelines for Americans, 2nd edition, provides information and guidance on the types and amounts of physical activity that provide substantial health benefits [ 2 ]. The evidence about the health benefits of regular physical activity is well established and so are the risks of sedentary behaviour [ 2 ]. Exercise is dose dependent, meaning that people who achieve cumulative levels several times higher than the current recommended minimum level have a significant reduction in the risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events [ 3 ]. Benefits of physical activity have been reported for numerous outcomes such as mortality [ 4 , 5 ], cognitive and physical decline [ 5 , 6 , 7 ], glycaemic control [ 8 , 9 ], pain and disability [ 10 , 11 ], muscle and bone strength [ 12 ], depressive symptoms [ 13 ], and functional mobility and well-being [ 14 , 15 ]. Overall benefits of exercise apply to all bodily systems including immunological [ 16 ], musculoskeletal [ 17 ], respiratory [ 18 ], and hormonal [ 19 ]. Specifically for the cardiovascular system, exercise increases fatty acid oxidation, cardiac output, vascular smooth muscle relaxation, endothelial nitric oxide synthase expression and nitric oxide availability, improves plasma lipid profiles [ 15 ] while at the same time reducing resting heart rate and blood pressure, aortic valve calcification, and vascular resistance [ 20 ].

However, the degree of all the above-highlighted benefits vary considerably depending on individual fitness levels, types of populations, age groups and the intensity of different physical activities/exercises [ 21 ]. The majority of guidelines in different countries recommend a goal of 150 min/week of moderate-intensity aerobic physical activity (or equivalent of 75 min of vigorous-intensity) [ 22 ] with differences for cardiovascular disease [ 23 ] or obesity prevention [ 24 ] or age groups [ 25 ].

There is a plethora of systematic reviews published by the Cochrane Library critically evaluating the effectiveness of physical activity/exercise for various health outcomes. Cochrane systematic reviews (CSRs) are known to be a source of high-quality evidence. Thus, it is not only timely but relevant to evaluate the current knowledge, and determine the quality of the evidence-base, and the magnitude of the effect sizes given the negative lifestyle changes and rising physical inactivity-related burden of diseases. This overview will identify the breadth and scope to which CSRs have appraised the evidence for exercise on health outcomes; and this will help in directing future guidelines and identifying current gaps in the literature.

The objectives of this research were to a. answer the following research questions: in children, adolescents and adults (both healthy and medically compromised) what are the effects (and adverse effects) of exercise/physical activity in improving various health outcomes (e.g., pain, function, quality of life) reported in CSRs; b. estimate the magnitude of the effects by pooling the results quantitatively; c. evaluate the strength and quality of the existing evidence; and d. create recommendations for future researchers, patients, and clinicians.

Our overview was registered with PROSPERO (CRD42019120295) on 10th January 2019. The Cochrane Handbook for Systematic Reviews of interventions and Preferred Reporting Items for Overviews of Reviews were adhered to while writing and reporting this overview [ 26 , 27 ].

Search strategy and selection criteria

We followed the practical guidance for conducting overviews of reviews of health care interventions [ 28 ] and searched the Cochrane Database of Systematic Reviews (CDSR), 2019, Issue 1, on the Cochrane Library for relevant papers using the search strategy: (health) and (exercise or activity or physical). The decision to seek CSRs only was based on three main aspects. First, high quality (CSRs are considered to be the ‘gold methodological standard’) [ 29 , 30 , 31 ]. Second, data saturation (enough high-quality evidence to reach meaningful conclusions based on CSRs only). Third, including non-CSRs would have heavily increased the issue of overlapping reviews (also affecting data robustness and credibility of conclusions). One reviewer carried out the searches. The study screening and selection process were performed independently by two reviewers. We imported all identified references into reference manager software EndNote (X8). Any disagreements were resolved by discussion between the authors with third overview author acting as an arbiter, if necessary.

We included CSRs of randomised controlled trials (RCTs) involving both healthy individuals and medically compromised patients of any age and gender. Only CSRs assessing exercise or physical activity as a stand-alone intervention were included. This included interventions that could initially be taught by a professional or involve ongoing supervision (the WHO definition). Complex interventions e.g., assessing both exercise/physical activity and behavioural changes were excluded if the health effects of the interventions could not have been attributed to exercise distinctly.

Any types of controls were admissible. Reviews evaluating any type of health-related outcome measures were deemed eligible. However, we excluded protocols or/and CSRs that have been withdrawn from the Cochrane Library as well as reviews with no included studies.

Data analysis

Three authors (HM, ALN, NK) independently extracted relevant information from all the included studies using a custom-made data collection form. The methodological quality of SRs included was independently evaluated by same reviewers using the AMSTAR-2 tool [ 32 ]. Any disagreements on data extraction or CSR quality were resolved by discussion. The entire dataset was validated by three authors (PP, MS, DP) and any discrepant opinions were settled through discussions.

The results of CSRs are presented in a narrative fashion using descriptive tables. Where feasible, we presented outcome measures across CSRs. Data from the subset of homogeneous outcomes were pooled quantitatively using the approach previously described by Bellou et al. and Posadzki et al. [ 33 , 34 ]. For mortality and quality of life (QOL) outcomes, the number of participants and RCTs involved in the meta-analysis, summary effect sizes [with 95% confidence intervals (CI)] using random-effects model were calculated. For binary outcomes, we considered relative risks (RRs) as surrogate measures of the corresponding odds ratio (OR) or risk ratio/hazard ratio (HR). To stabilise the variance and normalise the distributions, we transformed RRs into their natural logarithms before pooling the data (a variation was allowed, however, it did not change interpretation of results) [ 35 ]. The standard error (SE) of the natural logarithm of RR was derived from the corresponding CIs, which was either provided in the study or calculated with standard formulas [ 36 ]. Binary outcomes reported as risk difference (RD) were also meta-analysed if two more estimates were available. For continuous outcomes, we only meta-analysed estimates that were available as standardised mean difference (SMD), and estimates reported with mean differences (MD) for QOL were presented separately in a supplementary Table  9 . To estimate the overall effect size, each study was weighted by the reciprocal of its variance. Random-effects meta-analysis, using DerSimonian and Laird method [ 37 ] was applied to individual CSR estimates to obtain a pooled summary estimate for RR or SMD. The 95% prediction interval (PI) was also calculated (where ≥3 studies were available), which further accounts for between-study heterogeneity and estimates the uncertainty around the effect that would be anticipated in a new study evaluating that same association. I -squared statistic was used to measure between study heterogeneity; and its various thresholds (small, substantial and considerable) were interpreted considering the size and direction of effects and the p -value from Cochran’s Q test ( p  < 0.1 considered as significance) [ 38 ]. Wherever possible, we calculated the median effect size (with interquartile range [IQR]) of each CSR to interpret the direction and magnitude of the effect size. Sub-group analyses are planned for type and intensity of the intervention; age group; gender; type and/or severity of the condition, risk of bias in RCTs, and the overall quality of the evidence (Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria). To assess overlap we calculated the corrected covered area (CCA) [ 39 ]. All statistical analyses were conducted on Stata statistical software version 15.2 (StataCorp LLC, College Station, Texas, USA).

The searches generated 280 potentially relevant CRSs. After removing of duplicates and screening, a total of 150 CSRs met our eligibility criteria [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ] (Fig.  1 ). Reviews were published between September 2002 and December 2018. A total of 130 CSRs employed meta-analytic techniques and 20 did not. The total number of RCTs in the CSRs amounted to 2888; with 485,110 participants (mean = 3234, SD = 13,272). The age ranged from 3 to 87 and gender distribution was inestimable. The main characteristics of included reviews are summarised in supplementary Table  1 . Supplementary Table  2 summarises the effects of physical activity/exercise on health outcomes. Conclusions from CSRs are listed in supplementary Table  3 . Adverse effects are listed in supplementary Table  4 . Supplementary Table  5 presents summary of withdrawals/non-adherence. The methodological quality of CSRs is presented in supplementary Table  6 . Supplementary Table  7 summarises studies assessed at low risk of bias (by the authors of CSRs). GRADE-ings of the review’s main comparison are listed in supplementary Table  8 .

Study selection process

There were 54 separate populations/conditions, considerable range of interventions and comparators, co-interventions, and outcome measures. For detailed description of interventions, please refer to the supplementary tables . Most commonly measured outcomes were - function 112 (75%), QOL 83 (55%), AEs 70 (47%), pain 41 (27%), mortality 28 (19%), strength 30 (20%), costs 47 (31%), disability 14 (9%), and mental health in 35 (23%) CSRs.

There was a 13% reduction in mortality rates risk ratio (RR) 0.87 [95% CI 0.78 to 0.96]; I 2  = 26.6%, [PI 0.70, 1.07], median effect size (MES) = 0.93 [interquartile range (IQR) 0.81, 1.00]; 10 CSRs, 187 RCTs, 27,671 participants) following exercise when compared with various controls (Table 1 ). This reduction was smaller in ‘other groups’ of patients when compared to cardiovascular diseases (CVD) patients - RR 0.97 [95% CI 0.65, 1.45] versus 0.85 [0.76, 0.96] respectively. The effects of exercise were not intensity or frequency dependent. Sessions more than 3 times per week exerted a smaller reduction in mortality as compared with sessions of less than 3 times per week RR 0.87 [95% CI 0.78, 0.98] versus 0.63 [0.39, 1.00]. Subgroup analyses by risk of bias (ROB) in RCTs showed that RCTs at low ROB exerted smaller reductions in mortality when compared to RCTs at an unclear or high ROB, RR 0.90 [95% CI 0.78, 1.02] versus 0.72 [0.42, 1.22] versus 0.86 [0.69, 1.06] respectively. CSRs with moderate quality of evidence (GRADE), showed slightly smaller reductions in mortality when compared with CSRs that relied on very low to low quality evidence RR 0.88 [95% CI 0.79, 0.98] versus 0.70 [0.47, 1.04].

Exercise also showed an improvement in QOL, standardised mean difference (SMD) 0.18 [95% CI 0.08, 0.28]; I 2  = 74.3%; PI -0.18, 0.53], MES = 0.20 [IQR 0.07, 0.39]; 15 CSRs, 408 RCTs, 32,984 participants) when compared with various controls (Table 2 ). These improvements were greater observed for health related QOL when compared to overall QOL SMD 0.30 [95% CI 0.21, 0.39] vs 0.06 [− 0.08, 0.20] respectively. Again, the effects of exercise were duration and frequency dependent. For instance, sessions of more than 90 mins exerted a greater improvement in QOL as compared with sessions up to 90 min SMD 0.24 [95% CI 0.11, 0.37] versus 0.22 [− 0.30, 0.74]. Subgroup analyses by the type of condition showed that the magnitude of effect was the largest among patients with mental health conditions, followed by CVD and cancer. Physical activity exerted negative effects on QOL in patients with respiratory conditions (2 CSRs, 20 RCTs with 601 patients; SMD -0.97 [95% CI -1.43, 0.57]; I 2  = 87.8%; MES = -0.46 [IQR-0.97, 0.05]). Subgroup analyses by risk of bias (ROB) in RCTs showed that RCTs at low or unclear ROB exerted greater improvements in QOL when compared to RCTs at a high ROB SMD 0.21 [95% CI 0.10, 0.31] versus 0.17 [0.03, 0.31]. Analogically, CSRs with moderate to high quality of evidence showed slightly greater improvements in QOL when compared with CSRs that relied on very low to low quality evidence SMD 0.19 [95% CI 0.05, 0.33] versus 0.15 [− 0.02, 0.32]. Please also see supplementary Table  9 more studies reporting QOL outcomes as mean difference (not quantitatively synthesised herein).

Adverse events (AEs) were reported in 100 (66.6%) CSRs; and not reported in 50 (33.3%). The number of AEs ranged from 0 to 84 in the CSRs. The number was inestimable in 83 (55.3%) CSRs. Ten (6.6%) reported no occurrence of AEs. Mild AEs were reported in 28 (18.6%) CSRs, moderate in 9 (6%) and serious/severe in 20 (13.3%). There were 10 deaths and in majority of instances, the causality was not attributed to exercise. For this outcome, we were unable to pool the data as effect sizes were too heterogeneous (Table 3 ).

In 38 CSRs, the total number of trials reporting withdrawals/non-adherence was inestimable. There were different ways of reporting it such as adherence or attrition (high in 23.3% of CSRs) as well as various effect estimates including %, range, total numbers, MD, RD, RR, OR, mean and SD. The overall pooled estimates are reported in Table 3 .

Of all 16 domains of the AMSTAR-2 tool, 1876 (78.1%) scored ‘yes’, 76 (3.1%) ‘partial yes’; 375 (15.6%) ‘no’, and ‘not applicable’ in 25 (1%) CSRs. Ninety-six CSRs (64%) were scored as ‘no’ on reporting sources of funding for the studies followed by 88 (58.6%) failing to explain the selection of study designs for inclusion. One CSR (0.6%) each were judged as ‘no’ for reporting any potential sources of conflict of interest, including any funding for conducting the review as well for performing study selection in duplicate.

In 102 (68%) CSRs, there was predominantly a high risk of bias in RCTs. In 9 (6%) studies, this was reported as a range, e.g., low or unclear or low to high. Two CSRs used different terminology i.e., moderate methodological quality; and the risk of bias was inestimable in one CSR. Sixteen (10.6%) CSRs did not identify any studies (RCTs) at low risk of random sequence generation, 28 (18.6%) allocation concealment, 28 (18.6%) performance bias, 84 (54%) detection bias, 35 (23.3%) attrition bias, 18 (12%) reporting bias, and 29 (19.3%) other bias.

In 114 (76%) CSRs, limitation of studies was the main reason for downgrading the quality of the evidence followed by imprecision in 98 (65.3%) and inconsistency in 68 (45.3%). Publication bias was the least frequent reason for downgrading in 26 (17.3%) CSRs. Ninety-one (60.7%) CSRs reached equivocal conclusions, 49 (32.7%) reviews reached positive conclusions and 10 (6.7%) reached negative conclusions (as judged by the authors of CSRs).

In this systematic review of CSRs, we found a large body of evidence on the beneficial effects of physical activity/exercise on health outcomes in a wide range of heterogeneous populations. Our data shows a 13% reduction in mortality rates among 27,671 participants, and a small improvement in QOL and health-related QOL following various modes of physical activity/exercises. This means that both healthy individuals and medically compromised patients can significantly improve function, physical and mental health; or reduce pain and disability by exercising more [ 190 ]. In line with previous findings [ 191 , 192 , 193 , 194 ], where a dose-specific reduction in mortality has been found, our data shows a greater reduction in mortality in studies with longer follow-up (> 12 months) as compared to those with shorter follow-up (< 12 months). Interestingly, we found a consistent pattern in the findings, the higher the quality of evidence and the lower the risk of bias in primary studies, the smaller reductions in mortality. This pattern is observational in nature and cannot be over-generalised; however this might mean less certainty in the estimates measured. Furthermore, we found that the magnitude of the effect size was the largest among patients with mental health conditions. A possible mechanism of action may involve elevated levels of brain-derived neurotrophic factor or beta-endorphins [ 195 ].

We found the issue of poor reporting or underreporting of adherence/withdrawals in over a quarter of CSRs (25.3%). This is crucial both for improving the accuracy of the estimates at the RCT level as well as maintaining high levels of physical activity and associated health benefits at the population level.

Even the most promising interventions are not entirely risk-free; and some minor AEs such as post-exercise pain and soreness or discomfort related to physical activity/exercise have been reported. These were typically transient; resolved within a few days; and comparable between exercise and various control groups. However worryingly, the issue of poor reporting or underreporting of AEs has been observed in one third of the CSRs. Transparent reporting of AEs is crucial for identifying patients at risk and mitigating any potential negative or unintended consequences of the interventions.

High risk of bias of the RCTs evaluated was evident in more than two thirds of the CSRs. For example, more than half of reviews identified high risk of detection bias as a major source of bias suggesting that lack of blinding is still an issue in trials of behavioural interventions. Other shortcomings included insufficiently described randomisation and allocation concealment methods and often poor outcome reporting. This highlights the methodological challenges in RCTs of exercise and the need to counterbalance those with the underlying aim of strengthening internal and external validity of these trials.

Overall, high risk of bias in the primary trials was the main reason for downgrading the quality of the evidence using the GRADE criteria. Imprecision was frequently an issue, meaning the effective sample size was often small; studies were underpowered to detect the between-group differences. Pooling too heterogeneous results often resulted in inconsistent findings and inability to draw any meaningful conclusions. Indirectness and publication bias were lesser common reasons for downgrading. However, with regards to the latter, the generally accepted minimum number of 10 studies needed for quantitatively estimate the funnel plot asymmetry was not present in 69 (46%) CSRs.

Strengths of this research are the inclusion of large number of ‘gold standard’ systematic reviews, robust screening, data extractions and critical methodological appraisal. Nevertheless, some weaknesses need to be highlighted when interpreting findings of this overview. For instance, some of these CSRs analysed the same primary studies (RCTs) but, arrived at slightly different conclusions. Using, the Pieper et al. [ 39 ] formula, the amount of overlap ranged from 0.01% for AEs to 0.2% for adherence, which indicates slight overlap. All CSRs are vulnerable to publication bias [ 196 ] - hence the conclusions generated by them may be false-positive. Also, exercise was sometimes part of a complex intervention; and the effects of physical activity could not be distinguished from co-interventions. Often there were confounding effects of diet, educational, behavioural or lifestyle interventions; selection, and measurement bias were inevitably inherited in this overview too. Also, including CSRs only might lead to selection bias; and excluding reviews published before 2000 might limit the overall completeness and applicability of the evidence. A future update should consider these limitations, and in particular also including non-CSRs.

Conclusions

Trialists must improve the quality of primary studies. At the same time, strict compliance with the reporting standards should be enforced. Authors of CSRs should better explain eligibility criteria and report sources of funding for the primary studies. There are still insufficient physical activity trends worldwide amongst all age groups; and scalable interventions aimed at increasing physical activity levels should be prioritized [ 197 ]. Hence, policymakers and practitioners need to design and implement comprehensive and coordinated strategies aimed at targeting physical activity programs/interventions, health promotion and disease prevention campaigns at local, regional, national, and international levels [ 198 ].

Availability of data and materials

Data sharing is not applicable to this article as no raw data were analysed during the current study. All information in this article is based on published systematic reviews.

Abbreviations

Adverse events

Cardiovascular diseases

Cochrane Database of Systematic Reviews

Cochrane systematic reviews

Confidence interval

Grading of Recommendations Assessment, Development and Evaluation

Hazard ratio

Interquartile range

Mean difference

Prediction interval

Quality of life

Randomised controlled trials

Relative risk

Risk difference

Risk of bias

Standard error

Standardised mean difference

World Health Organization

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PP wrote the protocol, ran the searches, validated, analysed and synthesised data, wrote and revised the drafts. HM, NK and ALN screened and extracted data. MS and DP validated and analysed the data. RB ran statistical analyses. All authors contributed to writing and reviewing the manuscript. PP is the guarantor. The authors read and approved the final manuscript.

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Additional file 1:.

Supplementary Table 1. Main characteristics of included Cochrane systematic reviews evaluating the effects of physical activity/exercise on health outcomes ( n  = 150). Supplementary Table 2. Additional information from Cochrane systematic reviews of the effects of physical activity/exercise on health outcomes ( n  = 150). Supplementary Table 3. Conclusions from Cochrane systematic reviews “quote”. Supplementary Table 4 . AEs reported in Cochrane systematic reviews. Supplementary Table 5. Summary of withdrawals/non-adherence. Supplementary Table 6. Methodological quality assessment of the included Cochrane reviews with AMSTAR-2. Supplementary Table 7. Number of studies assessed as low risk of bias per domain. Supplementary Table 8. GRADE for the review’s main comparison. Supplementary Table 9. Studies reporting quality of life outcomes as mean difference.

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Posadzki, P., Pieper, D., Bajpai, R. et al. Exercise/physical activity and health outcomes: an overview of Cochrane systematic reviews. BMC Public Health 20 , 1724 (2020). https://doi.org/10.1186/s12889-020-09855-3

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Collection  15 May 2023

Editor's choice: exercise

Advances in exercise science have enabled increased optimisation of training and an enhanced performance for those taking part in sports, both professionally and recreationally. With this, we have also gained a greater understanding of the long-term health benefits conferred by sport, and the associated physiological changes. This Collection brings together papers which demonstrate recent advances in exercise science, from technological advancements in equipment and prosthetics, to innovative use of machine learning to analyse technique.

Performance

Differences in trunk and lower extremity muscle activity during squatting exercise with and without hammer swing

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Effects of plyometric and whole-body vibration on physical performance in collegiate basketball players: a crossover randomized trial

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• Moazzam Hussain Khan
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Circulating nitrate-nitrite reduces oxygen uptake for improving resistance exercise performance after rest time in well-trained CrossFit athletes

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Compression-induced improvements in post-exercise recovery are associated with enhanced blood flow, and are not due to the placebo effect

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• James R. Broatch

Impact of air pollution on running performance

• Marika Cusick
• Sebastian T. Rowland
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Effects of plyometric vs. strength training on strength, sprint, and functional performance in soccer players: a randomized controlled trial

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Progressive daily hopping exercise improves running economy in amateur runners: a randomized and controlled trial

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Comparison of finger flexor resistance training, with and without blood flow restriction, on perceptional and physiological responses in advanced climbers

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Health status of recreational runners over 10-km up to ultra-marathon distance based on data of the NURMI Study Step 2

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The integration of training and off-training activities substantially alters training volume and load analysis in elite rowers

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Injury Prevention & Recovery

Muscle coordination retraining inspired by musculoskeletal simulations reduces knee contact force

• Scott D. Uhlrich
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Impact of hip abductor and adductor strength on dynamic balance and ankle biomechanics in young elite female basketball players

• Fernando Domínguez-Navarro
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Difference in muscle synergies of the butterfly technique with and without swimmer’s shoulder

• Yuiko Matsuura
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Shoulder stretching versus shoulder muscle strength training for the prevention of baseball-related arm injuries: a randomized, active-controlled, open-label, non-inferiority study

• Hitoshi Shitara
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Health Benefits of Exercise

Affiliations.

• 1 Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211.
• 2 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65211.
• 3 Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri 65211.
• 4 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211.
• PMID: 28507196
• PMCID: PMC6027933
• DOI: 10.1101/cshperspect.a029694

Overwhelming evidence exists that lifelong exercise is associated with a longer health span, delaying the onset of 40 chronic conditions/diseases. What is beginning to be learned is the molecular mechanisms by which exercise sustains and improves quality of life. The current review begins with two short considerations. The first short presentation concerns the effects of endurance exercise training on cardiovascular fitness, and how it relates to improved health outcomes. The second short section contemplates emerging molecular connections from endurance training to mental health. Finally, approximately half of the remaining review concentrates on the relationships between type 2 diabetes, mitochondria, and endurance training. It is now clear that physical training is complex biology, invoking polygenic interactions within cells, tissues/organs, systems, with remarkable cross talk occurring among the former list.

Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

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Simplistic overview of how physical…

Simplistic overview of how physical activity can prevent the development of type 2…

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REVIEW article

Research advances in the application of metabolomics in exercise science.

• 1 School of Sport and Health, Shandong Sport University, Jinan, China
• 2 School of Exercise and Health, Shanghai University of Sport, Shanghai, China
• 3 School of Sport, Shenzhen University, Shenzhen, China

Exercise training can lead to changes in the metabolic composition of an athlete’s blood, the magnitude of which depends largely on the intensity and duration of exercise. A variety of behavioral, biochemical, hormonal, and immunological biomarkers are commonly used to assess an athlete’s physical condition during exercise training. However, traditional invasive muscle biopsy testing methods are unable to comprehensively detect physiological differences and metabolic changes in the body. Metabolomics technology is a high-throughput, highly sensitive technique that provides a comprehensive assessment of changes in small molecule metabolites (molecular weight <1,500 Da) in the body. By measuring the overall metabolic characteristics of biological samples, we can study the changes of endogenous metabolites in an organism or cell at a certain moment in time, and investigate the interconnection and dynamic patterns between metabolites and physiological changes, thus further understanding the interactions between genes and the environment, and providing possibilities for biomarker discovery, precise training and nutritional programming of athletes. This paper summaries the progress of research on the application of exercise metabolomics in sports science, and looks forward to the future development of exercise metabolomics, with a view to providing new approaches and perspectives for improving human performance, promoting exercise against chronic diseases, and advancing sports science research.

Introduction

A biomarker is a biological characteristic that can be measured and evaluated in an organism or a biological sample, and can be used to indicate the physiological state of an organism, disease risk, disease progression or treatment effect, and other information ( Qiu et al., 2023 ). Biomarkers can be molecules, cells, tissues, or physiological indicators, etc. Common biomarkers include genes, proteins, metabolites, hormones, and cell surface markers ( Di Minno et al., 2022 ). Metabolomics is the quantitative analysis of small molecular weight metabolites (molecular weight <1,500 Da) in organisms, such as carbohydrates, amino acids, organic acids, nucleotides, and lipids, using mass spectrometry or magnetic resonance spectroscopy, and by studying the pattern of change of organisms or endogenous metabolites at a given moment ( Kelly et al., 2020 ; Schranner et al., 2020 ; Belhaj et al., 2021 ; Shimada et al., 2021 ; Khoramipour et al., 2022 ). It is possible to investigate the interconnection and dynamic pattern of metabolites and physiological and pathological changes ( Kelly et al., 2020 ; Kistner et al., 2021 ). Metabolomics reflects the genome, transcriptome, and proteome, as well as their interactions with the environment, and provides an ideal way to measure organismal phenotypes ( Figure 1 ). Metabolomics data can provide useful insights into the biological effects of exercise, drug therapy, nutritional interventions, and more. Over the past decades, metabolomics has become a powerful tool for studying metabolic processes, identifying potential biomarkers, and deciphering metabolic reprogramming in various diseases to reveal the underlying mechanisms of relevant metabolic diseases ( Belhaj et al., 2021 ).

FIGURE 1 . Interconnections between metabolomics and the environment. Metabolomics reflects the genome, transcriptome, and proteome and their interactions with the environment.

Exercise can cause changes in the metabolism of many organs and tissues of the body, both acute and prolonged exercise, causing changes and adaptations in the body’s material metabolism and energy metabolism. Meanwhile, metabolites also regulate cellular signal release, energy transfer, and intercellular communication in the organism ( Monnerat et al., 2020 ; Schranner et al., 2020 ; Belhaj et al., 2021 ; Klein et al., 2021 ; Martins Conde et al., 2021 ). However, exercise physiology has traditionally only been able to study a small number of genes, proteins, and metabolites and their responses or adaptations to exercise, with no more than 12 metabolites measured using traditional methods and only one to two metabolic pathways at a time, failing to comprehensively detect exercise-induced physiological changes in tissues or metabolic pathways ( Belhaj et al., 2021 ; Khoramipour et al., 2022 ). The number of metabolites in the human body exceeds 110,000 compounds and the number of metabolic signaling pathways in the human body exceeds 40,000 ( Wishart et al., 2020 ). In addition, invasive muscle biopsies are required to collect metabolic data in exercise physiology studies ( Belhaj et al., 2021 ; Tokarz et al., 2021 ). While invasive muscle biopsies have successfully identified certain key metabolic pathways in the body, such as glycolysis and β-oxidation of free fatty acids, this invasive testing methodology limits the motivation of subjects to participate in the test and further limits the measurement of certain meaningful metabolic analyses, whereas the emergence of metabolomics has made it possible to conduct comprehensive, high-throughput, minimally or non-invasive metabolic studies in the field of exercise physiology ( Castro et al., 2020 ). This review briefly introduces the exercise metabolomics technology and workflow, focuses on the research progress of exercise metabolomics applied in the field of sports science, and looks forward to the future development direction of exercise metabolomics. The technique provides researchers with an effective research tool, which helps to improve the practical ability and depth of theoretical understanding of sports performance and chronic disease exercise control.

Introduction to exercise metabolomics

With the continuous development of histological techniques, exercise physiology is increasingly using metabolomics to probe organismal phenotypes, reveal metabolic pathways through the measurement of endogenous compounds, and identify biomarkers associated with exercise performance and fatigue, which has been termed “exercise metabolomics” ( Kelly et al., 2020 ; Zhou et al., 2021 ). In 2007, Pohjanen et al. (2007) introduced exercise metabolomics to exercise science by performing 90 min of stationary cycling on 24 healthy men, collecting blood samples for gas chromatography-mass spectrometry (GC-MS) analysis, and identifying 420 metabolites, of which 34 were significantly altered, with an emphasis on the role of the most valuable biomarkers (glycerol and asparagine), which demonstrated, for the first time, the potential of non-targeted GC-MS metabolomics to provide a useful tool for the identification of metabolic pathways associated with exercise performance and fatigue. Metabolomics by mass spectrometry may provide a comprehensive and unbiased approach to studying the metabolic effects of exercise interventions ( Pohjanen et al., 2007 ). Currently, the most commonly used biological samples in exercise metabolomics studies are blood and urine, and most studies use non-targeted metabolomics techniques, with mass spectrometry being the most commonly used detection and analysis platform in exercise metabolomics studies.

The main question in exercise science research is to understand how exercise induces physiological adaptations in the body, such as an increase in muscle strength or aerobic metabolic capacity, and how these adaptations affect health. But what are the molecular network mechanisms and metabolic pathways that govern how humans adapt to exercise and gain health benefits ( Sakaguchi et al., 2019 ; Blackburn et al., 2020 ; Febvey-Combes et al., 2021 ; Babu et al., 2022 )? These questions remain to be fully elucidated, and the study of exercise metabolomics will greatly enrich the understanding of these molecular network mechanisms and metabolic pathways.

Workflow of exercise metabolomics studies

As shown in Figure 2 , the workflow of exercise metabolomics research includes 1) identifying the biological question of the study; 2) developing a study design based on the biological question of the study; 3) collecting experimental samples; 4) preparing the samples; 5) analyzing the samples and acquiring the data using one or more analytical platforms; 6) statistically analyzing compounds based on the biological question and experimental design to determine metabolic differences between different groups of samples; 7) researchers use software tools and databases to integrate the detected compounds with the biological context to further enable metabolic pathway enrichment analysis, metabolite mapping, and visualization, which can help inform future research questions and experimental designs ( Belhaj et al., 2021 ; Khoramipour et al., 2022 ).

FIGURE 2 . Workflow of exercise metabolomics studies. The workflow of exercise metabolomics research mainly includes problem formulation, study design, sample collection, sample preparation, data collection, statistical analysis, and functional interpretation.

Sample collection and sample preparation

In human metabolomics research, the most common sample types are blood, urine, saliva, sweat, and fecal samples, with muscle biopsies and other types of tissue biopsies accounting for a lower percentage, and endogenous metabolites in the samples better reflect the physiological changes in the organism ( Kelly et al., 2020 ; Khoramipour et al., 2022 ). Sample type, sample quantity, and sample storage conditions are the keys to metabolomics experiments, each biological sample has advantages and disadvantages, the most commonly used types of biological samples in exercise metabolomics research are blood and urine, and the collection method is minimally invasive or non-invasive, and easy to be accepted by the subjects. Once collected, biological samples must be further processed or extracted to convert them into a state suitable for chemical analysis ( Khoramipour et al., 2022 ).

Chemical analysis platform and data analysis

Chemical analysis platforms used for sample characterization in metabolomics research include Gas Chromatography-Mass Spectrometry (GC-MS), Nuclear Magnetic Resonance (NMR), and Liquid Chromatography-Mass Spectrometry (LC-MS) ( Table 1 ) ( Kelly et al., 2020 ; Nicolaides et al., 2021 ; Khoramipour et al., 2022 ). The process of data processing and information analysis in metabolomics mainly includes the analysis of data, extraction of biological information, and functional interpretation of biological connotations ( Khoramipour et al., 2022 ). The data generated in metabolomics studies have multivariate characteristics, when the number of metabolites in a given sample reaches hundreds or thousands, multivariate analysis methods capable of dealing with related variables are required to achieve reliable comparisons between multiple samples based on the whole set of variables. For example, Principal Components Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA), and Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) ( Castro et al., 2020 ; Khoramipour et al., 2022 ).

TABLE 1 . Advantages and disadvantages of different chemical analysis methods.

Advances in exercise metabolomics research

There is a multifactorial dosage relationship between the effects of exercise on metabolic pathways, including the intensity of exercise, the duration of exercise, and the frequency of exercise ( Hargreaves and Spriet, 2020 ; Osawa et al., 2021 ). These factors can strongly influence the metabolic changes in the organism after exercise. In turn, the type and program of exercise, the level of exercise, and even exercise nutrition can also affect the body’s metabolism. In addition, the effect of exercise on the metabolomics of chronic diseases is also a current research hotspot, which provides new perspectives on the prevention and treatment of chronic diseases.

Effects of different exercise durations on body metabolism

There are some differences in the categories of metabolites induced in the body by different modes of exercise. For example, a short period of acute exercise can immediately cause changes in the metabolic pathways of skeletal muscle substrate utilization, and the changes in tricarboxylic acid (TCA) cycle metabolites are obvious after 1 h of exercise ( Kelly et al., 2020 ; Tabone et al., 2021 ). Amino acids such as leucine, isoleucine, asparagine, methionine, lysine, glutamine, and alanine decreased significantly after 14 h of exercise, reflecting the large magnitude of changes in amino acid levels after acute exercise ( Sakaguchi et al., 2019 ). Changes in plasma fatty acids, ketone bodies, bile acids, and triglycerides also showed changes that can last for several hours after acute exercise, eventually returning to pre-exercise levels ( Sakaguchi et al., 2019 ). For example, weight lifting and dumbbell training, resistance exercises such as pull-ups. Sakaguchi et al. found that within 24 h of a short period of acute exercise in the body, Significant changes in metabolites such as carbohydrates, TCA circulating metabolites, fatty acids, carnitine, ketone bodies, amino acids, and their derivatives were found ( Sakaguchi et al., 2019 ). Nayor et al. (2022) found that dimethylguanidinopentanoic acid and glutamate levels were reduced after a short period of acute exercise ( Nayor et al., 2022 ). Therefore, short-duration acute exercise can cause more substantial changes in metabolites related to energy metabolism.

Kujala et al. (2013) compared amino acid levels in several groups of twins who had been exercising consistently for several decades and found that the fatty acid composition of the long-term exercising population gradually shifted from a saturated to an unsaturated state and that glucose and isoleucine levels were lower ( Kujala et al., 2013 ). As shown in Figure 3 , changes in metabolites such as glucose, fatty acids, and triglycerides were observed in both long-term exercising and long-term non-exercising populations, but higher levels of fatty acids, triglycerides and cholesterol existed in long-term non-exercising populations, which are prone to chronic metabolic diseases such as dyslipidemia, hypertension, cardiovascular disease, stroke, type 2 diabetes and metabolic syndrome ( Mendham et al., 2021 ; Remie et al., 2021 ; McClain et al., 2022 ). However, people who exercise for a long period can accelerate the utilization of energy substances, reduce the accumulation of fat, and lower the levels of fatty acids, triglycerides, and cholesterol, which is conducive to the maintenance of healthy body weight as well as lowering the risk of chronic diseases ( Table 2 ) ( Tzimou et al., 2020 ; Bihlmeyer et al., 2021 ; Koay et al., 2021 ; Lemonakis et al., 2022 ). In the future, we will focus on the far-reaching effects of long-term exercise on weight loss and health.

FIGURE 3 . Comparison of metabolites between the long-term exercising population and the non-exercising population. The workflow of exercise metabolomics research mainly includes problem formulation, study design, sample collection, sample preparation, data collection, statistical analysis, and functional interpretation.

TABLE 2 . Effects of different exercise durations on key metabolites.

Effects of different exercise intensities on body metabolism

The most common metabolic pathways induced by exercise in the body are changes in fatty acid metabolism, fat mobilization, lipolysis, TCA cycle, glycolysis, amino acid metabolism, carnitine metabolism, purine metabolism, and cholesterol metabolism ( Kelly et al., 2020 ). Different exercise intensities have different effects on the body’s metabolism, with low-intensity aerobic training being dominated by aerobic metabolic pathways, with increases in the TCA cycle, fatty acid metabolism and amino acid metabolic pathways, and high-intensity resistance training being dominated by anaerobic metabolic pathways, with an increase in glycolysis and purine metabolism pathways ( Figure 4 ). The effect of exercise intensity on metabolic profiles was also present in outstanding athletes, Al-Khelaifi et al. (2018) collected blood samples from outstanding athletes in different sports and analyzed the changes in 743 metabolites based on an LC-MS platform, and found that outstanding athletes with low-intensity endurance training had higher levels of serum sex hormones (testosterone and progesterone), and lower levels of diacylglycerol and eicosanoids; while high-intensity strength-trained elite athletes had higher levels of phospholipids and xanthines ( Al-Khelaifi et al., 2018 ). Aerobic training mainly includes, running, cycling, football, and endurance sports such as swimming. Resistance training usually consists of high load, low repetition muscle contractions during a race ( Granacher et al., 2016 ). Examples include weightlifting training, polymetric training, or machine-based training that includes upper and lower body exercises such as squats, jumps, weighted sprints, push-ups, and pull-ups ( Fiorenza et al., 2019 ). This type of training is known to promote metabolic changes that facilitate anaerobic processes and increase muscle strength. Exercises such as gymnastics, martial arts and rock climbing also exhibit a high resistance component. In addition, endurance and resistance components are often combined, for example, in exercise interventions that combine running with weight training. Many sports also have significant endurance and resistance components, such as sprinting, boxing and rugby.

FIGURE 4 . Metabolites, metabolic pathways of different exercise intensity category interventions.

The type of sport also affects the body’s metabolic differences, such as marathons, track, boxing, cycling, football, rowing, rugby swimming, etc. There are differences in metabolic changes in different sports, and the reason for metabolic differences in different sports is mainly due to the different proportion of the energy supply system, such as weightlifters with the phosphate energy supply system, rowers with the glycolysis energy supply system, and marathon athletes with the aerobic oxidative energy supply system ( Al-Khelaifi et al., 2018 ). Even the metabolism of athletes in different positions in the same sport varies, e.g., there are metabolic differences between football goalkeepers and field players participating in the same game, and these differences are likely to be caused by exercise intensity and exercise duration ( Blackburn et al., 2020 ; Schader et al., 2020 ; Bester et al., 2021 ; Pugh et al., 2021 ). In addition, athletes in endurance sports have significantly increased levels of glycolytic products, TCA cycle intermediates, nucleotide metabolites, acylcarnitines, and branched-chain amino acids, which are frequently associated with aerobic metabolic pathways. Resistance training studies have shown significant increases in levels of creatine, choline, guanidine acetate, and hypoxanthine and decrease in creatinine levels in athletes in strength and explosive events, metabolites that are commonly associated with muscle growth, intracellular buffering, and methyl regulation ( Khoramipour et al., 2022 ).

Effects of different levels of exercise on the body’s metabolism

The level of exercise also affects the body’s metabolic differences, and Enea et al. used metabolomics for the first time to differentiate between metabolite changes in trained and untrained women, who underwent a 75% maximal oxygen uptake test, and then collected urine samples to analyze the metabolite changes based on an NMR platform, and found that the metabolites of creatine, lactic acid, pyruvic acid, alanine, β-hydroxybutyric acid, acetate, and hypoxanthine significant differences between groups ( Enea et al., 2010 ).

Not only is there a difference in metabolism between trained and untrained individuals, but also the same athletes and different levels of exercise affect metabolism. Schader et al. (2020) found that slower marathon runners with lower levels of aerobic metabolism capacity had drastically altered levels of metabolites, with significant changes in phospholipids and amino acids ( Schader et al., 2020 ). In contrast, the metabolomic alterations in good athletes were characterized by higher levels of phosphatidylcholine after the race ( Høeg et al., 2020 ). San-Millan et al. (2020) found increased levels of circulating metabolites in TCA and elevated amplitude of lactate accumulation in good cyclists ( San-Millán et al., 2020 ). In addition, Prado et al. collected urine samples from football players and analyzed their metabolic changes during competition based on an LC-MS platform, identifying 1,091 metabolites, of which 526 metabolites showed significant changes, including significant increases in the levels of glucose, uric acid urea, fatty acyls, carboxylic acids, steroids and steroid derivatives, and significant decreases in the levels of potassium ( Khoramipour et al., 2022 ). Hudson et al. (2021) based on an NMR platform analyzed the metabolite changes in blood, urine, and saliva samples of outstanding rugby players, and found that the energy metabolism pathways of rugby, as a sport with high exercise intensity, mainly include glycolysis, TCA cycle, and gluconeogenesis ( Hudson et al., 2021 ). Moreira et al. (2018) analyzed the urinary metabolites of outstanding swimmers and found that creatine, ketone bodies, phosphate, and nitrogen-containing compounds can be used as urinary metabolites to assess the outstanding swimmers’ exercise performance, which can be accurately assessed. Athletes’ performance, which can accurately assess their physiological status and provide a scientific basis for the development of athletes’ training load programs ( Moreira et al., 2018 ).

The effect of sports nutrition on the body’s metabolism

Kirwan et al. (2009) found that post-exercise intake of sugars and caffeine and analysis of metabolite changes in blood samples based on an NMR platform revealed a significant decrease in blood glucose levels, a significant increase in ketone body levels, and a significant increase in plasma levels of lactic acid and alanine (required for gluconeogenesis), which is the first study of sports nutrition metabolomics ( Kirwan et al., 2009 ). Kozlowska et al. (2020) explored the effects of beetroot juice supplementation on the metabolism of fencing, and urine samples were collected to identify changes in metabolites based on an LC-MS platform, and significant changes in the metabolism of tyrosine, tryptophan, epinephrine, and norepinephrine were detected, which can help provide a scientific basis for the development of training load programs for athlete ( Kozlowska et al., 2020 ). Yan et al. (2018) investigated the modulatory effects of ginseng supplementation on the metabolic patterns of professional athletes and explored the mechanism of ginseng’s antifatigue effects. Their metabolite analysis of blood samples from athletes based on a GC-MS platform revealed that American ginseng significantly modulated serum metabolism, significantly decreasing serum creatine kinase and blood urea nitrogen levels ( Yan et al., 2018 ). Cronin et al. (2018) explored the effects of physical activity and protein intake on gut microbial composition and function, and genomics and metabolomics evaluations revealed significant changes in gut microbial composition and function with increased physical activity, with the gut virome significantly changing with increased physical activity in participants who received daily supplementation with whey protein ( Cronin et al., 2018 ). Among participants receiving daily whey protein supplementation, the diversity of the gut virome changed significantly, suggesting that exercise and nutrition can significantly influence the composition and function of the gut microbiota. Therefore, metabolomics serves as an assessment tool to facilitate the design of personalized and fine-tuned exercise training and nutritional guidance programs for athletes, which can help to maximize athletic performance. In addition, Zhang et al. (2020) explored the effects of a 6-month exercise and dietary intervention on serum metabolites in men with insomnia symptoms, collecting blood samples from subjects for metabolite analysis based on a GC-MS platform, and found that the effects of exercise on sleep were mainly related to amino acid, carbohydrate and lipid metabolism, whereas the effects of diet on sleep were related to carbohydrate, lipid and organic acid metabolism ( Zhang et al., 2020 ). Thus, metabolomics provides new insights into the effects of physical activity and diet on sleep quality.

Exercise metabolomics in chronic disease prevention and treatment research

Contrepois et al. (2020) analyzed more than 600 metabolite changes in blood samples collected based on an LC-MS platform using a variety of histological approaches (targeted and untargeted metabolomics, lipidomics, proteomics, and transcriptomics), and showed that exercise has a significant effect on energy metabolism, oxidative stress, inflammation, tissue repair and its regulatory pathways in diabetic patients ( Contrepois et al., 2020 ). Shi et al. (2019) found that Exercise can alter myocardial and skeletal muscle metabolism in heart failure model rats, and the metabolic pathways of taurine and hypotaurine metabolism and carnitine synthesis have a certain regulatory effect on alleviating heart failure, thus providing an effective target for the treatment of patients with heart failure ( Shi et al., 2019 ). Siopi et al. (2019) studied the effect of exercise training with different intensities on male patients with metabolic syndrome and collected blood samples to analyze the changes of metabolites based on the LC-MS platform ( Siopi et al., 2019 ). They found that resistance training induced the strongest metabolic changes, and the metabolites of branched-chain amino acids, alanine, carnitine, choline, and betaine had larger changes, indicating that exercise has beneficial effects on important serum biomarkers in patients with metabolic syndrome, which can help optimize the exercise guidelines for the people with risk of metabolic syndrome and improve the exercise prescription ( Siopi et al., 2019 ). Palmnas et al. (2018) analyzed the blood samples of obese people based on the NMR platform and found that the obese people had the best metabolite changes. Blood samples and found that serine and glycine concentrations were lower in the obese population, which can help to find molecular targets for the treatment of chronic metabolic diseases in obese populations ( Palmnäs et al., 2018 ). Liu et al. (2021) collected blood samples from children with metabolic syndrome and analyzed the changes in metabolites based on the LC-MS platform, and found that exercise combined with dietary interventions induced 59 metabolites (glycine, serine, and threonine metabolisms, nitrogen metabolism, TCA cycling, and phenylalanine, tyrosine, and tryptophan biosynthesis, etc.) to changes, thus providing early diagnostic biomarkers for the treatment of metabolic diseases such as obesity ( Liu et al., 2021 ).

Analysis of metabolic pathways by exercise

Exercise training induces changes in the body’s metabolic pathways such as lipid metabolism, TCA cycle, glycolysis, amino acid metabolism, carnitine metabolism, and purine metabolism ( Kelly et al., 2020 ). Positive effects on cardiovascular health and mitochondrial biogenesis exist in populations that engage in chronic low-intensity aerobic training, where energy is produced through oxidative phosphorylation ( Rivera-Brown and Frontera, 2012 ). Therefore, the activation of aerobic metabolic pathways and the increase in the TCA cycle, fatty acid β-oxidation metabolism and amino acid metabolism pathways, which allows for the presence of lower levels of fatty acids, triglycerides, and cholesterol in the organism, can accelerate the utilisation of energy substances and reduce the accumulation of fat, which is conducive to the maintenance of a healthy body weight as well as reducing the risk of chronic diseases, in addition to increasing the variety of energy substances burned during exercise ( Pellegrino et al., 2022 ). Chronic metabolic adaptations in prolonged exercise populations typically affect metabolic pathways such as glycolysis, protein synthesis, amino acid consumption, and nucleotides.

In addition to improving muscle strength and metabolic health with short bursts of high-intensity resistance training, it also induces muscle hypertrophy. Resistance training is associated with metabolic changes that contribute to improved anaerobic capacity, muscle health, and glycolytic metabolism ( Krzysztofik et al., 2019 ). Resistance training is mainly dominated by anaerobic metabolic pathways, with an increase in glycolytic and purine metabolic pathways. One of the most significant metabolic adaptations induced by resistance training is the increase in protein synthesis and depletion of amino acids, which are necessary to increase muscle mass ( Shen et al., 2021 ; Gehlert et al., 2022 ). In addition, the pathways involved in nucleotide synthesis—the production of RNA, DNA and phospholipids required for cellular membranes—are activated ( Pellegrino et al., 2022 ). There is an increase in the rate of ATP hydrolysis and the rate of nucleotide turnover, an increase in the accumulation of lactic acid in metabolites following acute resistance training and an increase in the ability to promote glycolytic metabolic adaptations ( Gehlert et al., 2022 ). Metabolic adaptations in elite athletes are characterised by increased fuel substrate utilisation, fatty acid β-oxidation, oxidative stress, steroid biosynthesis and protein anabolic pathways ( Cai et al., 2022 ).

Physical activity has many benefits for both physical and mental health, as studied through metabolomic analysis of metabolites released from tissues such as skeletal muscle, bone and liver. These metabolites can influence the body’s metabolic adaptations and improve cardiovascular health, reduce inflammation and increase muscle mass. Aerobic training increases mitochondrial content and oxidative enzymes, while resistance training increases muscle fibres and glycolytic enzymes. Acute exercise leads to changes in amino acid metabolism, lipid metabolism and cellular energy metabolism as well as cofactor metabolism and vitamin metabolism. Chronic exercise leads to changes in amino acid metabolism, lipid metabolism and nucleotide metabolism and improves lipid metabolism, thereby improving cardiovascular risk factors and skeletal muscle adaptations. The study of exercise-induced metabolites is a growing field with the potential to reveal more metabolic mechanisms and tailor exercise programs for optimal health and exercise performance.

Potential limitations of exercise metabolomics

Many early exercise metabolomics studies lacked statistical rigor, e.g., extensive use of multivariate statistics, small sample sizes, and a single platform for metabolic analyses ( Khoramipour et al., 2022 ). Furthermore, there were deficiencies in the sensitivity and specificity of the biomarkers used in most exercise metabolomics studies ( Schranner et al., 2021 ). With the continuous advancement of histological technologies, metabolomics data alone may not be sufficient to fully characterize complex physiological changes. There is still potential for further improvements in the study design of many exercise metabolomics studies. In particular, exercise-related parameters or measurements, such as exercise intensity and exercise duration, have a strong influence on metabolic changes after exercise training. Researchers should incorporate and quantify these parameters more consistently in study designs, which would facilitate comparisons between studies. Another important goal of exercise metabolomics research is to routinely use and integrate more histological (proteomics, genomics, transcriptomics) techniques in study design. Metabolomics should not be an “island,” and the integration of multi-omics data will help researchers to further understand the interactions between genes, proteins, metabolites, and the environment, and to gain a deeper understanding of the effects of exercise on the organism.

Summary and outlook

Exercise metabolomics provides researchers in the field of exercise science with an effective research tool to search for potential biomarkers and therapeutic targets by detecting metabolite changes in a variety of biological fluids and tissues after exercise in athletes and patients with chronic diseases, thus helping to improve the practical ability and depth of theoretical understanding of exercise performance and exercise prevention and treatment of chronic diseases.

With the continuous maturation of the technology and the deepening of the research, future exercise metabolomics research will further evaluate the exercise performance of outstanding athletes, so that their physiological conditions can be accurately assessed, which will provide a scientific basis for the development of precise training load programs for athletes and help coaches to cultivate outstanding athletes in a more effective way. In addition, mass spectrometry-based metabolomics testing is important for the treatment of metabolic disorders and provides clinicians with effective targets for the treatment of metabolic disorders, which is helpful for the treatment of chronic metabolic disorders. Meanwhile, mass spectrometry-based metabolomics studies will cover more subjects and will identify more metabolites. It is expected that more points of interest will emerge in the field of exercise metabolism and sports nutrition, focusing on the use of metabolomics findings to further design personalized and precise nutritional regimens to maximize the health benefits of physical performance and exercise. Finally, from the category of research groups, exercise metabolomics should focus more on human studies and more on practical orientated, reality-based experimental designs, collecting non-invasive sample collection methods based on urine and saliva. Such a trend will make exercise metabolomics research more informative and popular with participants, and lead to better and more accessible research tools for researchers, athletes, and coaches.

Author contributions

SQ: Writing–original draft. XL: Writing–review and editing. JY: Writing–review and editing. LY: Writing–review and editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by a grant from the key program of Shandong Institute of Physical Education Research Start-up Funds (No. 2390015).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: metabolomics, exercise, metabolism, nutrition, biomarkers

Citation: Qi S, Li X, Yu J and Yin L (2024) Research advances in the application of metabolomics in exercise science. Front. Physiol. 14:1332104. doi: 10.3389/fphys.2023.1332104

Received: 02 November 2023; Accepted: 27 December 2023; Published: 15 January 2024.

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Copyright © 2024 Qi, Li, Yu and Yin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jinglun Yu, [email protected] ; Lijun Yin, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Research in the Exercise Sciences

Where we are and where do we go from here-part ii.

Baldwin, Kenneth M.; Haddad, Fadia

Department of Physiology and Biophysics, University of California-Irvine, Irvine, CA, United States

Address for correspondence: Kenneth M. Baldwin, Ph.D., FACSM, Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697 (E-mail: [email protected] ).

Accepted for publication: October 19, 2009.

Associate Editor: Stephen M. Roth, Ph.D., FACSM

This decadal perspective summarizes novel, insightful observations achieved in exercise science. The topics span genomics and gene function, epigenetics, cell signaling, epidemiological phenomena, and other important areas. A future strategy is presented along two parallel, integrated paths involving the following: 1) a continuance of genomic discovery and gene function, and 2) classical biochemical/physiological approaches toward solving biological- and health/disease-related phenomena.

This article summarizes novel findings in exercise science in the last decade and points to new directions in the future.

INTRODUCTION

In 2000, a perspective was provided concerning the evolution of the "exercise sciences" in the 21st century ( 4 ). The article covered a wide range of topics such as the following: 1) emerging technologies and research initiatives, 2) new fields of research, 3) future funding trends and research priorities, 4) future challenges in exercise research-the building of a solid foundation, and 5) where the exercise sciences fit in health care.

Well, here we are 10 yr later, and the current authors have been charged with the assignment of taking the pulse concerning the scope of progress that has been made in the exercise field in the last 10 yr along with projecting what impact such accomplishments bode for the future. Although the goal of this perspective will be essentially the same as before, we will take a slightly different tactic in formulating such a view. Rather than providing only our personal opinion, several experts in the field were contacted to provide their own insights. The responses received were quite insightful, and there was a large degree of agreement in their respective viewpoints.

In the present article, the goal is to examine to what degree progress has been made on several fronts in the exercise field. Based on the dialogue presented below, it is not surprising that considerable advancements have occurred in skeletal muscle, given the fact that it is the organ system of exercise/movement. Then, we will posture how the exercise field should evolve. Hopefully, such an approach will provide a reflection of what the science community has accomplished and how we can extend the knowledge base down the road. Furthermore, we apologize in advance for not providing more depth and breadth in covering topics beyond those highlighted in this perspective (see next section).

SELECTED HIGHLIGHTS AND NOVEL DISCOVERIES IN THE LAST 10 YR

Before going into the details, it is important to point out some general background information. A PubMed search with the word exercise retrieved approximately 82,826 peer-reviewed articles published in the past 10 yr. There were approximately 3836 papers linked to genetics, 45 to proteomics, 155 to genomics, 22 to epigenetics, and 326 to signaling pathways. For additional links to the exercise theme, the term obesity retrieved 7357 articles; diabetes, 6312; longevity, 254; muscle, 18,562; bone, 4038; metabolism, 24,033; nervous system, 4505; hormones, 6954; brain function, 2644; circulation, 3426; immune system, 1281; respiratory, 5734; and hematology, 126. These data suggest a wide range of subject matter linked to the exercise sciences and illustrate a vast group of investigators focusing on these important topics. Unfortunately, the authors cannot cover all these mentioned themes, given the strict space constraints for this brief perspective.

Achievements in Gene Function and Regulation

Genomics, genetic factors, and exercise.

The Human Genome Project was completed in 2003. No doubt, this milestone helped pave the way for genomic research exploring how genetic factors impact the responses and adaptations of health-related traits to exercise stimuli. Furthermore, studies have identified polymorphism in more than 239 genes and quantitative trait loci (QTL) and associated certain genotypes with cardiovascular responses, fitness phenotypes, and muscle strength and power adaptations ( 8 ). For example, there is a strong association between R577X genotype of the alpha actinin 3 gene ( ACTN3 ) and performance in a variety of athletic endeavors. The R allele has been found to be associated with power-oriented performance, whereas the XX genotype may be linked with endurance ability ( 49 ). However, the collective data point to the fact that, although some genotypes may be associated with certain phenotypes, the overall physiological significance is multifactorial, and the result of interactions between the genome, the epigenome, and the environment widely vary on an individual basis. Thus, this evolving field has generated a wide diversity of viewpoints as to how the field will evolve as pointed out by the excellent perspective provided by Stephen Roth, Ph.D., FACSM ( 42 ). He predicts that genomic studies will continue to enhance our understanding of the underlying biology of exercise responses. Genomic information can be useful for prescribing individualized exercise regimen especially when treating susceptible patients. No doubt, exercise genomics, applied in public health care, will be a hot area in the next decade.

Gene knockouts

In the last 10 yr, the molecular manipulation of gene function, designed almost exclusively for the mouse, has exploded with a large number of the articles recently published in the last 2 yr. The primary approach has been to null out a target gene and address the likely physiological and biochemical outcomes (phenotype) in the context of either acute or chronic exercise performance. The genes that have been studied span a broad scope, as illustrated by the following genes examined: triacylglycerol lipase, insulin-like growth factor-1 (IGF-1), peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC1-alpha), adenosine monophosphate (AMP) related kinases, desmin, vascular endothelial growth factor (VEGF), tumor protein P53, carnitine functional interruption, muscular dystrophy (MDX), alpha 1 AMP kinase, uncoupling protein-3 (UCP3), LOV keltch protein (LKP) kinase, thrombospondin-1 (TSP-1), myoglobin, myostatin, adenine nucleotide translocator, and hypoxia inducible factor-1 alpha to name a few.

To illustrate the power of this research approach, the function of TSP-1 will be illustrated as reported by Malek and Olfert ( 28 ). This gene is a negative modulator of angiogenesis in several tissue types. Animals with this gene knocked out have greater muscle capillarity and a corresponding greater running endurance capacity than the wild-type animals. This study thus provides a unique insight that the capillary-to-muscle interface is a critical factor that limits exercise capacity. Importantly, this article points out that the negative consequences of the loss of TSP-1 also must be considered because there are checks and balances to maintain optimal levels of physiological processes whether it is blood supply regulation or cell growth. In the context of the recent review article by Booth and Laye ( 7 ), this study would have been more complete if the animals also were studied under increased daily physical activity. Gene function may differ between inactive animals and those with high levels of daily physical activity ( 7 ). For example, with certain gene knockouts, animals fail to show the disease phenotype when the animals have access to voluntary wheel running ( 7 ). Thus, for a full spectrum of gene function, knockout animals should be compared with wild type not only at rest but also under chronic exposure to physical activity and in response to an acute exercise stress stimulus ( 7 ).

RNA interference

RNA interference (RNAi) is the process of sequence-specific posttranscriptional gene silencing, initiated by double-stranded RNA that is identical in sequence to the target gene. The discovery that synthetic duplexes of 21 nucleotides (siRNAs) trigger gene-specific silencing in mammalian cells has made them a useful tool to study gene function in mammalian systems ( 16,26 ). SiRNA technology involves the use of small interfering RNA fragments that can be delivered into cells either directly or via a plasmid vector delivery system. Once within the cell, siRNAs trigger the degradation of their cognate messenger RNA (mRNA), thereby reducing the substrate for translation. Thus, the target gene becomes significantly "knocked down," thereby reducing the effectiveness of the target gene's regulation of physiological processes. This technology is theoretically simpler and more cost effective than genetically producing the "knockout" approach and is particularly useful in studying the function of genes that are lethal upon complete knockout. Another advantage of siRNA usage is that because the target protein is not completely eliminated, the knockdown perturbations are less likely to induce compensatory plasticity processes observed with complete knockouts. Consequently, in the future, siRNA is predicted to be used in a broad range of experiments targeting the rat because of its long-standing use as an important animal model in the exercise field.

Epigenetics and gene regulation

Epigenetics is a new and rapidly growing research field that investigates heritable alterations in chromosome function/gene expression caused by mechanisms other than changes in DNA sequence. Epigenetic mechanisms are diverse but can be classified into three interacting areas involving the following: modulation of the chromatin/histone structure (methylation, acetylation, and phosphorylation), DNA methylation, and noncoding RNA such as microRNA and antisense RNA (reviewed in ( 30 )). Recent studies have shown that epigenetic modulations also can be dynamically and rapidly occurring in response to environmental changes to alter gene expression. For example, our group, in carrying out recent studies on the plasticity of the myosin heavy chain (MHC) gene family in response to altered loading state, has discovered two types of epigenetic phenomena. The first involves the expression of antisense RNA in the fast MHC gene locus in which the MHC genes are organized in tandem on the same chromosome. These antisense RNAs allow adjacent genes to cross talk as well as to coordinate regulation of neighboring MHC genes ( 35,41 ). Second, we have discovered that repression of slow MHC and activation of fast MHCs (and vice versa) in a given muscle involve altered patterns of acetylation and methylation of the histones that regulate expression of MHCs, that is, slow to fast and fast to slow depending on the loading conditions ( 36 ).

Recently, epigenetic regulation was linked to rat behavior in response to exercise. It was shown that exercise causes epigenetic changes that lead to enhanced memory formation and better coping in response to stress. Significant increases in histone H3 phosphoacetylation and induction of the cFos gene were found in the brain of exercised rats ( 11 ). Another epigenetic inducer is diet. For example, recently, a high-fat diet was shown to increase methylation of the leptin gene, thus reducing its expression in obese people ( 31 ). These findings raise the possibility that many of the adaptations that occur in muscle and in other organ systems in response to diet, exercise, chronic inactivity, aging, and many disease interventions could be regulated, in part, via epigenetic phenomena. These observations lead to an important topic for future investigation, which suggests the possibility that the beneficial effects of exercise is occurring via epigenetic reprogramming of gene expression. The notion that environmentally induced epigenetic traits have an impact on future generations has important ramifications for future research involving diet and exercise. For example, can diet and exercise induce specific epigenetic modulations that serve as a countermeasure for many disorders, which helps in overcoming our genetic weakness and predisposition to certain diseases ( 7 )?

Micro-RNAs (miRNA) are small noncoding RNAs that regulate gene expression at the posttranscriptional level ( 44 ). These highly conserved ∼21-mer RNAs regulate the expression of genes by binding to the 3'-untranslated regions (3'-UTR) of specific mRNA. Each individual miRNA could act posttranscriptionally to target hundreds of mRNAs for translational repression, degradation, or destabilization. They are involved in many aspects of cell function and play a significant role in disease development. Research suggests that miRNAs are major regulators of gene expression and thus are part of the adaptive response ( 10 ). Computational analyses continue to identify gene targets for cellular miRNA; however, these targets must be validated with microarray data. MiRNAs together with transcription factors generate a complex combinatorial code regulating gene expression. There is speculation that, in higher eukaryotes, the role of miRNAs in regulating gene expression could be as important as that of transcription factors. Thus, identifying and targeting miRNA-transcription factor gene networks may provide a potent approach in future research in exercise science as applied to therapy and disease prevention.

Genetic selection and maximal exercise performance

The relative contribution of genetic and environmental influences in terms of individual exercise capacity is difficult to determine in humans. In recent studies using self-selected rodents after many generations (7 vs 15), it was possible to delineate key factors for determining maximal oxygen consumption rate (MOCR) in inherent high capacity runners (HCR) versus low capacity runners (LCR) independent of training stimuli. In generation 7 animals, MOCR was primarily differentiated between the two groups by the ability of the muscle system to extract and diffuse oxygen rather than the capacity to deliver oxygen. In generation 15, the opposite was apparent in that the HCR again had greater MOCR than LCR, but the difference in this generation was due to greater oxygen delivery rather than greater oxygen extraction. In both generations, the HCR group had greater oxygen diffusion capacity. According to P.D. Wagner and associates ( 21 ), these unique studies are important in that they now allow researchers to dissect each step in the transport chain while also eliminating the environmental factors' contribution to these physiological phenomena.

Cell Signaling: Regulatory Molecules Impacting Metabolism and Muscle Mass

Muscle metabolism.

One of the long-standing questions in all fields of biomedical science involves filling in the gap between the stimulus and response to a given perturbation, for example, exercise (aerobic and/or resistance loading). In the last decade, major strides have occurred in filling in such gaps, and this is illustrated by a couple of examples, although there are numerous signaling pathways that control physiological and immune homeostasis. In the metabolic fields relative to exercise, the signaling pathway centered on adenosine monophosphate kinase (AMPK) has shown that by activation of this so-called fuel gauge or metabolic regulator (pharmacological and contraction-induced activation), a number of outcomes occur in association with AMPK activation ( 47 ). These include increases in glucose disposal; fatty acid oxidation; activating transcriptional regulators of mitochondrial biogenesis; and mediating actions of hormones such as leptin, adiponectin, and glucocorticoids. Interestingly, AMPK also serves as a negative modulator of anabolic processes (glycogen, fatty acid, and protein synthesis). Thus, AMPK is a powerful regulatory molecule, and in the future, it will likely be the target of various pharmacological interventions for treating various disorders centered on diabetes and obesity. In this context, we have witnessed the controversy of using pharmacological manipulation of AMPK function and its downstream targets (PPAR-delta and PGC1-alpha) as presented in the findings of Narker et al. on the improvement of exercise performance via an exercise "pill" ( 34 ). This article has created several counter viewpoints as to the physiological impact and merit of such an approach as reviewed in the excellent article by Booth and Laye ( 7 ).

Mitochondrial biogenesis

Forty-two years ago, Holloszy ( 18 ) made a seminal discovery that programmed running exercise carried out over several weeks induces a doubling of the mitochondria in the leg muscles of rodents not normally accustomed to physical activity. Since that time, hundreds of studies have focused on this important phenomenon, which serves as one of the key linchpins that define the field of muscle plasticity. Fast forward to this decade, several studies as reviewed by Holloszy ( 19 ) and Hood ( 20 ) provide the mechanism(s) driving this important discovery. For example, studies have shown that a single bout of exercise induces a rapid increase in mitochondrial biogenesis that is mediated by PGC1-alpha and other factors, which induce transcription of both nuclear and mitochondrial genes that combine to encode the protein comprising the mitochondria ( 3,25 ). This important discovery has rejuvenated the science community such that mitochondrial research in health, disease, and aging will be a major focus in the next decade. In fact, a new field of science referred to as "mitochondrial medicine" has emerged.

Muscle mass

Another important discovery/advancement of similar importance involves the IGF-1 protein kinase B/AKT-mTOR (mammalian target of rapamycin) signaling pathway, which has been linked to anabolic processes, particularly in skeletal muscle in response to exercise ( 6 ). This pathway has been shown to activate a number of downstream effectors that act on enhancing expression of the ribosomal translation machinery, as well as increasing activity of activators and enzyme systems in the processes governing protein translation as well as immune function. Furthermore, this system is linked to inhibiting processes Forkhead box O1 (Foxo1-Atrogin-1 MAFbx system) governing the catabolic processes of protein degradation ( 29,32,43 ). There are several other signaling pathways that have been dissected and worthy of being mentioned, but lack of space prevents such a dialogue in this brief review.

In the context of the above topics concerning signaling for metabolic regulation and the regulation of anabolic pathways for controlling muscle mass, a perspective has evolved suggesting that if the signaling pathway for metabolic control is activated, the pathway(s) for anabolic outcomes is down regulated and vice versa ( 2,12 ). This incompatibility seems counterintuitive to some degree because many athletes train for enhanced functional capacity for both properties. Clearly, research in the future is needed to address this important topic.

Muscle as an Endocrine Organ System

In recent years, Pedersen et al. ( 37 ) coined the term myokine for any factor apparently expressed/synthesized in skeletal muscle in response to physical activity, which in turn can act either locally or released into the blood to regulate function in other tissues. Three myokines have been identified and partially characterized. Interleukin (IL)-6 seems to act both locally on carbohydrate metabolism and distally on hormone activity in the pancreas/liver and in lypolysis in adipose tissue. IL-8 acts locally and may play a key role on angiogenic processes. IL-15, which is released during resistance exercise ( 40 ), seems to regulate anabolic processes in skeletal muscle. Interestingly, individuals expressing certain single nucleotide polymorphism in the IL-15 receptor-alpha demonstrated more muscle hypertrophy than other subjects in response to resistance exercise training ( 40 ). These collective observations illustrate that this emerging field is ready to explode and will have a major impact on how we view the role of skeletal muscle in terms of being a regulator of function in other organ systems ( Figure ).

The Dynamics of Connective Tissue and Bone Adaptation With Exercise

The study of connective tissue in regard to both tendon and the intramuscular connective tissue recently has blossomed to the forefront partly because of the efforts of Mackey et al. ( 27 ). It has been demonstrated that the metabolism, blood flow, and turnover of collagen in connective tissue is rapid and that regulatory factors are up regulated in relation to exercise (IGF-1, transforming growth factor (TGF-beta, IL-6)). By use of microdialysis and stable isotopes, ultrasonography, and atomic force microscopy, these various approaches have made it possible to determine the structure and function of this dynamic tissue along with examining the adaptive regulation in response to various activity paradigms. The consensus of these findings is that the connective tissue infrastructure responds to exercise stimuli as rapidly as the myofiber complex.

With regard to physical activity and the anabolic responses of bone, it seems that the response varies among different skeletal elements and across different regions of the same bone according to the recent findings of Hamrick et al . ( 15 ). Their findings on treadmill running mice for only 30 min·d −1 suggest that the osteogenic responses of cortical bone to exercise varies significantly along the length of a bone, and more distal regions seem most likely to exhibit morphological changes when loading conditions are altered. The mechanisms for this heterogeneity have not been elucidated.

On the front of genetic and environmental factors contributing to bone mass, Suuriniemi and coworkers ( 45 ) investigated the role of PvuII polymorphism in the estrogen receptor (ER)-alpha gene concerning the activity profiles on 245 prepubertal and early pubertal girls, given that impairment of bone mass at puberty is an important risk factor for osteoporosis in later life. Their findings suggest that the PvuII polymorphism in the ER-alpha gene may modulate the effect of exercise on bone mineral density at loaded sites. The heterozygotes seem to benefit most from the exercise effect; whereas, neither of the homozygote groups received any significant improvement from physical activity. The findings further suggest that physical activity may hide the genetic effect on bone; for example, one may compensate one's less favorable Pp genotype by increasing physical activity at early puberty. It would be interesting to determine in future research whether these exercise-induced effects are occurring via epigenetic reprogramming.

The Role of Progenitor (Satellite) Cells in Muscle Adaptation

Skeletal muscle fibers (cells) are unique in that they are multinucleated and also maintain satellite cell pools in the basal lamina. Whether myonuclear addition from the satellite cell pool is a prerequisite for marked skeletal muscle fiber enlargement to occur in response to loading stimuli is the subject of ongoing inquiries in the muscle biology field. Petrella et al. ( 38 ) addressed this topic by using cluster analyses of 66 subjects that underwent a rigorous quadriceps resistance exercise training program. The subjects were subsequently classified after training into three groups of fiber enlargement: 1) extreme responders, 2) moderate responders, and 3) nonresponders. Extreme responders had more nuclei per fiber before training and showed the greatest level of satellite cell expansion and incorporation into the enlarged myofibers as compared with both the moderate and non responders. These observations provide strong evidence that myonuclear proliferation/differentiation is a prerequisite for load-induced fiber enlargement in human muscle. These findings on human muscle essentially corroborate previous studies on rodent skeletal muscle that were overloaded for long duration after irradiation to prevent satellite cell proliferation/differentiation. In that study, irradiation prevented the marked hypertrophy that was observed in nonirradiated muscle as well as the incorporation of satellite cells in the muscle's nuclear domain ( 1 ). Moreover, there is additional evidence that injury repair processes also are dependent on satellite cell proliferation in the repair of injured/ regenerating fibers.

Exercise and Endothelial Cardiovascular Biology

The crucial role played by the endothelium (the lining cells of blood vessels) in cardiovascular biology is becoming increasingly appreciated as endothelial dysfunction seems to have detrimental consequences and long-term effects. For example, endothelial injury has been implicated in atherosclerosis, thrombosis, and hypertension. During the last 10 yr, it has become evident that endothelial progenitor cells (EPCs), released from bone marrow, may play an important role in maintaining an intact endothelial cell layer ( 33 ). Earlier reports from animal experiments suggest that circulating EPCs bind to the activated dysfunctional epithelium via specific receptors and reconstitute the endothelial cell layer by secretion of mediators of proliferation ( 39 ). Recent research also suggests that acute exercise stimulates release of EPCs in steady-state strenuous exercise along with other regulatory factors such as VEGF and IL-6. Additionally, reports by Brehm et al. ( 9 ) provide strong evidence that physical activity predisposes the mobilization and enhanced functional activity of circulating progenitor cells that may lead to improved cardiovascular function in patients with recently acquired myocardial infarct. Finally, Witkowski et al. ( 48 ) report that chronic long-duration exercise training in aging male subjects demonstrated greater hyperemic forearm blood flow compared with less active subjects, although the EPC counts were not different between the two groups. Additionally, detraining of the active subjects resulted in both a large decrease in reactive forearm blood flow and circulating EPCs and VEGF receptor number. These alterations were correlated to changes in antioxidant capacity. These collective findings clearly point to the important role that exercise plays in maintaining the homeostasis of the vascular endothelial system and the dynamic nature of its response to inactivity.

Epidemiological Studies on Physical Activity and Longevity

In the last decade, there have been many articles published pointing to the positive impact that physical activity plays in the evolution of several degenerative diseases such as cardiovascular dysfunction, diabetes, metabolic syndrome, and osteoporosis to name a few. In fact, studies show that physical exercise is "more protective" than might be predicted on exercise-induced changes in risk factors ( 23 ). However, the critical question is whether exercise plays a positive role in extending one's life span. In 2001, Blair and colleagues ( 5 ) set the tone by trying to sort out whether it was physical activity per se or the level of fitness that contributed to health benefits leading to longevity because both were linked to reducing morbidity from coronary heart disease, stroke, cardiovascular disease, certain types of cancer, and all-cause mortality. It was recommended that future studies define more precisely the shape of the dose-response gradient across activity and the level of fitness groups with a primary focus on musculoskeletal fitness relative to additional health outcomes. Although ongoing research suggests that activity level is an important contributor to longevity for both male and female subjects, only recently did new insight occur on this important topic by focusing more on elite athletes. Recently, Teramonto and Bungum ( 46 ) analyzed mortality and longevity of elite athletes using a variety of standardized tests. Their findings show that elite endurance (aerobic) athletes and mixed-sport (aerobic and anaerobic) athletes survive longer than the general population, as indicated by lower mortality and higher longevity. Furthermore, the results point to lower cardiovascular disease as the primary factor for these lower mortality rates. On the other hand, there are inconsistent results among studies on power (anaerobic) athletes. Thus, there is some truth to the term survival of the fittest.

To put this important issue into a broader perspective, Fraser and Shavlik ( 13 ) studied 34,192 California Seventh-Day Adventists and found that this subject pool has higher life expectancy than other white Californians by approximately 7.28 yr, giving them the highest expectancy of any formally described population. Additional analyses attributed this life extension to diet (leaning toward more vegetarian), exercise, lower body mass index, less dependency on hormone replacement, and lack of smoking. It might turn out that, in the long run, it is the behavioral choices that individuals make that contribute to one's longevity.

Biomedical Informatics

Biomedical informatics (BMI) is an expanding field that is playing an ever growing role in health care and biomedical research. BMI now encompasses subdisciplines such as bioinformatics, imaging informatics, clinical informatics, and public health informatics ( 14 ). Indeed, electronic medical record systems and numerous National Institutes of Health (NIH) initiatives like the Clinical Translational Science Award place a heavy emphasis on biomedical informatics. A fundamental component of biomedical informatics is the so-called ontology, which provides a controlled vocabulary and set of terminologies that can be used to model a domain of knowledge or discourse. Currently, an exercise/physical activity/physical inactivity specific ontology does not exist. Consequently, it is our recommendation that recognized organizations in the field of exercise science like the American College of Sports Medicine take the lead in developing ontologies that will play an essential role in accelerating breakthroughs in the field of exercise science.

MOVING FORWARD ON TWO PATHS

Building on a solid foundation.

With the topics covered above, it is clear that research initiatives in the last decade were focused heavily on gene discovery and gene expression, along with their manipulation and regulation. These new areas of study were enhanced further by the emergence of the epigenetic field. New technologies blossomed and became commonly available such that it became easier to perform molecular/biochemical analyses via kits purchased off the shelf from a large variety of vendors (which, in turn, generated a lot of junk mail). Furthermore, a wide variety of high throughput analyses systems became available in many areas in the biological sciences to include genomics, proteomics, and epigenetics. These, in turn, generated a "mountain" of data that required advances in the bioinformatics field to design software for better analyses and integration of the large volume of data being generated. Thus, it is safe to say that the research centered around "gene expression and function" will only get bigger and better as more information is generated and integrated in different fields, including the exercise sciences. However, is this path the only way to go?

Back to the Future: The Essence of Fundamental Biochemistry

In a recent opinion/OP-ED article in the New York Times ( www.nytimes.com/2009/08/06/opinion/06watson.html?_r=1 ) Nobel Laureate, James D. Watson, provided a deep rooted perspective on the topic: "To Fight Cancer, Know the Enemy." Watson opined that over the years since 1971, the NIH National Cancer Institute squandered the assault on fighting cancer by putting more resources into comprehensive cancer centers rather than putting needed money into basic cancer research. Although the death rates for cancer have dropped over time, the cure for cancer is nowhere on the horizon.

Watson points out that a comprehensive overview of how cancer biology works did not begin to emerge until about 2000, with more extensive details about specific cancers beginning to pour forth only after the completion of the Human Genome Project in 2003. At present, although there are promising drugs in the pipeline, these "powerful attackers" may not be effective for every case and for a life long cure. Watson postulates that the time has come to turn the focus away from decoding the genetic instructions behind cancer and to a greater degree toward understanding the "chemical reactions within cancer cells." This concept is based on the long-standing discoveries of biochemists that cancer cells, to grow and replicate, are almost exclusively dependent on the metabolic processes of carbohydrate metabolism, which "overdrive" reactions that lead to increased glucose transportation into these rapid growing cells to fuel the signaling driving proliferation differentiation processes. Thus, Watson argues the need to return to performing studies on the biochemistry of cells to ascertain the function and mechanisms of gene products. In the authors' view, there are potential lessons learned from the Watson opinion piece that can be translated to the exercise sciences in dealing with a number of degenerative diseases and health epidemics.

For example, we are well aware of the critical problems associated with obesity, which seems to keep growing despite a lot of attention by the science community. Perhaps it is time to get back to basics. This is illustrated by the unique studies recently published by Huber et al. ( 22 ). They have made the unique observation that by undernourishing (caloric restriction) pregnant rats, the development of the fetus is imprinted with a biochemical footprint favoring the economy of energy balance. After birth, the animals grow normally in the neonatal state, but as they proceed into adulthood, they become obese, although they do not consume more food than their normal sibling counterparts. Also, these animals prefer exercise relative to food intake if presented with the choice, and exercise proves to be useful in preventing the development of obesity in this model. Furthermore, the biochemical cascade of this process is much different in its biochemical mechanism as compared with normal animal littermates that were fed high fat diets and also became obese.

To put these above findings into a human context, in a report by Kyle and Pichard ( 24 ) involving the Dutch famine of 1944-1945, prenatal famine due to marked food reduction in pregnant mothers resulted in significant alterations in physiological homeostasis of the offspring. These included increases in impaired glucose tolerance, obesity, coronary heart disease, atherogenic lipid profiles, antisocial personality, and other related disorders. These unique findings point to the importance of using modern tools to dissect the signaling processes and the biochemical framework for understanding obesity and other disorders in different types of animal models and potentially in humans with different prenatal, neonatal developmental, genetic, and epigenetic imprints. Furthermore, the above phenomena raises important questions for maternal fetal programming of exercise effects; for example, will physically active mothers have more physically active offspring? Or will such offspring have some protection against inactivity-related disorders?

In the Figure, we present a conceptual framework of integrating the physiology/biochemistry with genomic data as an approach for better interpretation of data in exercise physiology and potential outcomes.

Some Key Themes Driving the Exercise Science Field in the Future

The following topics listed below were provided by investigators who responded to the inquiry. They are by no means the end-all of where the science should be heading.

• Exercise mimetics: the controversial article of Narker et al. ( 34 ) has sparked keen interest into whether there are a wide range of pharmacological agents (exercise pills) that can activate certain pathways linked to enhancing running capacity and/or muscle growth. The key question is whether exercise stimuli are essential requirements to enhancing physical fitness and improved metabolic outcomes. See the reviews of Booth and Laye ( 7 ) on this controversial topic as well as the article by Hawley and Holloszy ( 17 ), the latter of which puts exercise mimetics in proper perspective.
• Studies are already unfolding to search for large numbers of single nucleotide polymorphisms and invariant genomic probes to unlock genomic variation contributing to fitness, performance, and trainability. These probing breakthroughs are made possible by both human and mouse genotyping arrays generated by collaborations between Jackson Laboratories and Affymetrix (note that the authors have no financial conflicts of interest on these technology advancements).
• Reactive oxygen species: the focus will be to understand the underlying biology of these species, including their role in regulating muscle mass under different impacting loading state and as signaling molecules for organelle, organ, and organismal adaptations.
• Genomics: the genomic basis of muscle function is already expanding (because of new technologies) to gain insights on athletic performance, general health, and the exercise impact on different diseases.
• The muscle from inside and out: the role of myokines, cytokines, and adipokines are thought to impact both organ systems and organism homeostasis; the new emphasis should focus on mechanisms driving such synergism.
• The processing of substrate fuels during acute and chronic exercise in athletic, sedentary, and obese lifestyles.
• Experiments need to be designed to ascertain the mechanism(s) of cell signaling regulation when aerobic and anabolic training paradigms are simultaneously imposed on animal and human subjects.
• Muscle fiber, connective tissue, bone, and satellite cell integration: each of these systems is dynamic and the challenge is to understand their integrative role in responses to various mechanical stimuli.
• Mechanical sensors and signaling regulators that control muscle size: this area is largely unexplored.
• Discovering biomarkers for predicting exercise and altered health settings: it is accepted that there is a large variability in how humans respond to different types of training stimuli; is it possible to predict who are the responders versus nonresponders?
• Extreme environments: there are many challenges to frame the underlying mechanisms as to how individuals perform in stressful environments of heat, cold, hypoxia, and insufficient nutrition.
• The link between exercising muscle and brain plasticity: this is possibly the key to the real quality of life in the aging population.
• Exercise and disease prevention: probably the biggest challenge for impacting the health industry in the next decade and beyond.
• Mechanisms regulating aging and exercise-induced longevity: the real bottomline to exercise research endeavors.

In the context of the above topics, it is important to note that several of the previous possible future research topics may involve epigenetic research to answer some critical questions that could not be solved with basic genomic approaches.

BUDGET TRENDS: ARE THE NECESSARY RESOURCES AVAILABLE TO COMPLETE THE MISSION?-NOT

In 2000, the NIH's operational budget was $22 billion (B). It increased further to $30 B by 2003 as part of the "budget doubling package" initiated previously by Congress in the late 1990s. From that point on to the present time, the budget has remained flat; and with corrections for inflation, the actual operating dollars has steadily fallen in excess of 10%. This budget profile has had a marked negative effect on NIH funding for investigator initiated R0 types of grant applications. In some of the NIH institutes, the pay line percentages are approaching single digits.

In 2009, the Obama administration, as part of the stimulation package initiative, infused $8.4 B into the NIH budget for scientific priorities in the form of Challenge Grants in Health Science Research (these grants are supposed to provide 2 yr of funding but with no opportunity for renewal). Also, in many of the NIH institutes, there was an infusion of money into the typical R01 type of grant, which has the potential to elevate transiently the funding level for a short period (2009 and 2010). Presently, as this article is being written, there is no assurance that the funding profile will be enhanced to a higher steady-state level in real dollars beyond the 2010 budget. Also, to the authors' knowledge, with so many applications being submitted in the Challenge Grant initiative (∼20,000), it is highly unlikely that many individuals in the exercise sciences field benefited from the stimulus package initiative. This is punctuated by the fact that the pay line for most of the grants was in the second to third percentile! Thus, unless there is a dedicated stimulus to the NIH budget down the road that provides a continuous increase in the operational budget that exceeds the cost of inflation with a primary target toward R0 grant applications, the authors are pessimistic concerning the potential of enhancing the research mission well beyond that which has occurred up until the present time.

From our perspective, investigators working in the field of exercise science and its related fields have made outstanding strides on many fronts as illustrated by the examples delineated in this perspective. This occurred despite funding limitations during the latter half of this decade. Despite this funding fiasco, there is an amazing database and an assortment of state-of-the-art technologies, analytical tools, and sets of resources that posture the community for bigger and better things to come. However, unless appropriate stimulating packages and stable budget profiles return to viable levels, 10 yr from now, the report card or progress report will not reach its true potential.

The authors thank the following individuals who contributed their insights and suggestions to the composition of this article: Greg Adams, Marcas Bamman, Claude Bouchard, Vince Caiozzo, Michael Kjaer, Mark Olfert, Bente Klarlund Pedersen, Steve Roth, Michael Sawka, Stefano Schiaffino, Espen Spangenburg, Ron Terjung, Peter Wagner, and William Winder.

This article was supported in part by NIH grants AR-30348 and HL-73473.

gene regulation; muscle as an endocrine organ; epigenetics; cell signaling; biochemistry; epidemiology; obesity

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New science shows how exercise affects nearly every cell in the body

Many Americans start off each new year with resolutions to lose weight , and gym memberships typically rise in January. But by March, the resolutions often have been dropped. The pounds didn’t melt away as expected, and the gym shoes get kicked to the back of the closet.

While exercising may help people lose weight and maintain the weight loss, fitness experts say, people might overestimate how many calories they burn when they are working out, or they simply may not do enough to move the scale. That 30-minute cardio workout that left you sweaty and breathless may have felt like a grueling marathon, but it may have burned only 200 to 300 calories.

“That can be completely undone by consuming one donut in like, what, 60 seconds,” said Glenn Gaesser, a professor of exercise physiology at the College of Health Solutions at Arizona State University in Phoenix. “So we can undo with eating in a matter of minutes what it took us to burn that many calories over the course of many, many minutes, sometimes hours.”

Regular exercise offers many benefits beyond burning calories — so there are plenty of reasons to keep moving in the new year. “Research shows that exercise affects pretty much every cell in the body, not just our heart, not just our muscles, but it also affects all the other organs, as well,” Gaesser said. “Exercise is something that is vital for good health.”

We have found that exercise basically improves health outcomes largely independent of weight loss.

Glenn Gaesser, Arizona State University, Phoenix

Among the benefits listed by the Centers for Disease Control and Prevention are sharper thinking, less depression and anxiety, better sleep, help with weight management, stronger bones and muscles, and reduced risks of heart disease, stroke, diabetes and cancers of the breast, the colon and other organs.

To obtain “substantial health benefits,” federal health guidelines advise adults to do at least 150 to 300 minutes a week of moderate-intensity physical activity or 75 to 150 minutes a week of vigorous physical activity, or an equivalent combination.

Nina McCollum, 52, of Cleveland, said she began gaining weight after she had a baby at age 40. The weight gain accelerated more in the last few years, said McCollum, who mainly blamed menopause.

McCollum, who has been physically active throughout her life, didn’t find that exercise helped keep the extra pounds off. She now considers herself about 40 pounds overweight, but she’s as much of an exercise enthusiast as ever. She works out at home, doing calisthenics and weight training and running stairs. She also walks her dog, and on the weekends she goes for outdoor hikes.

“I don’t care anymore that I’m not like a stick figure,” she said. Instead, she is focused on staying fit, strong and flexible as she ages, keeping healthy and trying to ward off heart disease, which runs in her family.

Exercise to live longer

Gaesser said research shows that people who are overweight but exercise regularly, like McCollum, still reap many health benefits. “We have found that exercise basically improves health outcomes largely independent of weight loss,” he said.

Physical activity works on multiple mechanisms within the body, and that’s how it could potentially help prevent chronic conditions and therefore also prevent early deaths.

Amanda Paluch, University of Massachusetts Amherst

He co-wrote an article published in iScience in October that reviewed multiple studies and compared weight loss to exercise for promoting longevity and improving people’s overall health.

While most of the data were based on observational studies and can’t be used to establish cause and effect, Gaesser said, the research suggests that intentional weight loss is associated with a reduction in mortality risk of 10 percent to 15 percent. By comparison, studies suggest that increasing physical activity or improving fitness is associated with a reduction in mortality risk in the range of 15 percent to 60 percent.

“The major take-home message is that just being physically active and trying to improve your fitness seems to provide better prospects for longevity than just trying to lose weight,” he said.

Another study published last year also found that exercise promotes longevity — even walking significantly fewer than the often recommended 10,000 steps. Middle-age people who walked at least 7,000 steps a day on average were about 50 percent to 70 percent less likely to die of cancer, heart disease or other causes over the next decade than those who walked less, according to results in JAMA Open Network.

“Physical activity works on multiple mechanisms within the body, and that’s how it could potentially help prevent chronic conditions and therefore also prevent early deaths,” said the study’s author, Amanda Paluch, an assistant professor of kinesiology at the University of Massachusetts Amherst.

Dr. Robert Sallis has long viewed exercise as a critical part of a healthy lifestyle. As president of the American College of Sports Medicine from 2007 to 2008, he inspired the “ Exercise is Medicine ” campaign, which encourages physicians to talk to patients about their physical activity, even to “prescribe” it.

Sedentary people who get moving can start feeling better right away, said Sallis, a clinical professor of family medicine at the University of California, Riverside, School of Medicine and the director of the sports medicine fellowship at Kaiser Permanente in Fontana.

“The first thing is mental health. That is almost the first thing people notice — I feel better, I have more energy, I sleep better,” he said. “But then you could just go down the list of chronic diseases. I couldn’t tell you a disease that isn’t helped by it, from diabetes to heart disease to blood pressure to cholesterol to cancer, on and on.”

Sallis encourages patients who don't exercise to start small and try to work up to the federal guidelines.

"The curve is very steep in terms of the benefits,” he said. “Doing just a little bit gives tremendous benefits. So I try to focus on those smaller pieces instead of feeling like you have to join a gym and you have to do all this. Just go out and walk."

He also encourages patients to keep going even if they aren’t losing weight . Too often, there is “this singular focus on their weight and thinking that, you know, if I don’t lose weight, the exercise was not helpful to me, and a lot of them use that as a reason to stop,” he said. “But the weight has so little to do with the benefits. If you can get patients who are overweight to be active, they get the same health benefits.”

And being thin doesn’t mean you don’t need to exercise.

“In fact, if you’re at a normal weight and you aren’t physically active, you’re putting yourself at risk for a lot of conditions,” Sallis said.

NBC News contributor Jacqueline Stenson is a health and fitness journalist who has written for the Los Angeles Times, Reuters, Health, Self and Shape, among others. She also teaches at the UCLA Extension Writers' Program.

Effects of Exercise Intervention on Physical and Mental Health of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis Based on ICF-CY

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• Published: 08 August 2024

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• Lili Feng   ORCID: orcid.org/0000-0002-5311-3688 1   na1 ,
• Bowen Li 1   na1 ,
• Su Sean Yong 1 &
• Zhenjun Tian   ORCID: orcid.org/0000-0002-8747-6161 2  

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Attention deficit/hyperactivity disorder (ADHD) affects the physical and mental health in children and adolescents. Evidence suggests that participation in exercise may benefit children and adolescents with ADHD and enhance current and future physical and mental health. This systematic review and meta-analysis investigated the effects of exercise interventions on the physical and mental health of children and adolescents with ADHD, based on the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY) framework.

This review systematically searched for studies published up to August 1, 2023, through PubMed, Web of Science, PsycINFO, and Scopus. A meta-analysis was performed on studies that reported physical and mental health outcomes more than 10 times. A semiquantitative analysis was performed on studies that reported those indicators less than 10 times. In addition, all physical and mental health outcome indicators were linked to ICF-CY codes.

A total of 43 studies were included in the systematic review, 13 of which were eligible for meta-analysis. Our meta-analysis results showed that levels of anxiety and depression significantly decreased after exercise intervention, with medium (Hedges’ g  = − 0.63, 95% CI [1.17, − 0.09], P  < 0.05) and large effect sizes (Hedges’ g  = − 1.03, 95% CI [− 1.94, − 0.12], P  < 0.05), respectively. The level of attention problem significantly decreased after exercise intervention, with a large effect size (Hedges’ g  = − 1.28, 95% CI [− 2.59, 0.04], P  = 0.06), but no statistical difference was observed. The level of motor skills significantly improved after exercise intervention with a large effect size (Hedges’ g  = 0.97, 95% CI [0.42, 1.51], P  < 0.01). The level of muscle strength significantly improved after exercise intervention, with a small effect size (Hedges’ g  = 0.37, 95% CI [0.05, 0.68], P  < 0.05). The included studies covered a total of 31 outcome indicators, which could be divided into 4 one-level classifications and 27 two-level classifications according to the ICF-CY framework. Among the outcome indicators, 21 (67.74%) were related to “physical functions”, 9 (29.03%) were related to “activities and participation”, and 1 (3.23%) was related to “body structures”.

This study confirmed that exercise could improve the physical and mental health in children and adolescents with ADHD. Regarding exercise intervention to improve the health of children and adolescents with ADHD, existing research has focused on verifying the immediate effect of intervention from the perspective of “physical functions”. However, there is a lack of in-depth exploration into changes in the dimensions of “body structures” and “activities and participation”, as well as the long-term intervention effects. Future studies should focus more on a holistic view of health that considers “body structures and functions” and “activities and participation”, which could ultimately favor comprehensive and long-term improvements in the health status of children and adolescents with ADHD.

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Lili Feng and Zhenjun Tian conceptualized this work; Lili Feng, Bowen Li, and Su Sean Yong conducted literature searches, evidence synthesis, and data analysis; Lili Feng, Bowen Li, and Su Sean Yong performed records screening and data extraction; Lili Feng wrote the manuscript; Su Sean Yong critically edited the manuscript. All authors have contributed to reading and approving the final manuscript. Lili Feng and Bowen Li share the first authorship. Bowen Li and Zhenjun Tian are the co-corresponding authors.

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Feng, L., Li, B., Yong, S.S. et al. Effects of Exercise Intervention on Physical and Mental Health of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis Based on ICF-CY. J. of SCI. IN SPORT AND EXERCISE (2024). https://doi.org/10.1007/s42978-024-00295-8

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Exercise Science M.S.

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• In the M.S. program, you'll examine how physical activity affects physiological systems.
• You'll build upon core courses in exercise science, research, and statistical thinking, with focused electives that interest you, such as training, environmental physiology, health, aging, disease, and more.
• Then, you'll put your skills into practice and choose from an intensive research project (master’s thesis) or an immersive internship experience to prepare you for your career goals.

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David B. Falk College of Sport and Human Dynamics

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This program provides the theoretical background and practical experience needed for students pursuing national certifications offered by the American College of Sports Medicine and the National Strength and Conditioning Association . You'll have the option to complete an internship or partake in a master’s thesis.

Internship: Gain Significant Field Experience

For the internship experience option, you’ll practice and learn under the guidance of a site supervisor—a full-time professional at your internship site—and a faculty mentor. There are a wide variety of internship settings in Syracuse, including three major hospitals within walking distance of campus, local private practice settings, Syracuse University Athletics, and other local professional and collegiate sports teams.

Master’s Thesis: Make an Impact Through Research

For the master’s thesis option, you will complete a research project, from data collection and analysis, to presenting your findings and submitting your work, to academic journals for publishing. Research in exercise science impacts health policies, patient treatment plans, nutritional recommendations, athletic training, community interventions, health access and equity initiatives, and beyond.

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The Department of Exercise Science houses several laboratories that support integrative research at the cellular, tissue, and whole organism level. Laboratories include:

• The Cardiovascular Laboratory: Conducts non-invasive assessment of vascular structure and function to explore the impact of exercise on emerging markers of cardiovascular disease risk.
• The Kinesmetrics Laboratory : Apply objective measurement tools to understand physical behaviors’ (sleep, sedentary behavior and physical activity) consequences on health.
• The Clinical Research Laboratory : Utilize metabolic testing facilities and wet lab space to measure cardio-metabolic risk factors—such as insulin resistance, metabolic syndrome, and type 2 diabetes—in obese populations.
• The Hypoxia/Altitude Simulation Laboratory: Assess the role of low oxygen (hypoxia) on human physical performance using a high-altitude simulation chamber.

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No matter your unique research interest, your project will have every opportunity to thrive under the guidance of faculty mentors at Syracuse University. Exercise science faculty are widely published, leading scholars supported by grant funding from the National Institutes of Health, National Science Foundation, American College of Sports Medicine, National Aeronautics and Space Administration (NASA), and more.

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With an M.S., you can practice exercise physiology in many settings, such as:

• Government, hospital-based, and non-profit health programs (including cardiac rehabilitation units).
• Corporate fitness and personal training.
• Research and instructor roles in higher education or healthcare.

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• Physician’s assistant, occupational therapy, physical therapy, or nursing.
• Advanced study in exercise science (our Ph.D. program or related doctoral programs in kinesiology nationwide), a national fitness certification, medical school, or another area of interest.

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Good Scientific Practice and Ethics in Sports and Exercise Science: A Brief and Comprehensive Hands-on Appraisal for Sports Research

Nitin kumar arora.

1 Department of Intervention Research in Exercise Training, German Sport University Cologne, 50933 Cologne, Germany

2 Department of Physiotherapy, University of Applied Sciences, 44801 Bochum, Germany

Golo Roehrken

Sarah crumbach.

3 Institute of Sport Economics and Sport Management, German Sport University Cologne, 50933 Cologne, Germany

Ashwin Phatak

4 Institute of Exercise Training and Sport Informatics, German Sport University Cologne, 50933 Cologne, Germany

Berit K. Labott

5 Institute of Sport Sciences, Otto-von-Guericke University, 39106 Magdeburg, Germany

André Nicklas

Pamela wicker.

6 Department of Sports Science, Bielefeld University, 33615 Bielefeld, Germany

Lars Donath

Associated data.

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Sports and exercise training research is constantly evolving to maintain, improve, or regain psychophysical, social, and emotional performance. Exercise training research requires a balance between the benefits and the potential risks. There is an inherent risk of scientific misconduct and adverse events in most sports; however, there is a need to minimize it. We aim to provide a comprehensive overview of the clinical and ethical challenges in sports and exercise research. We also enlist solutions to improve method design in clinical trials and provide checklists to minimize the chances of scientific misconduct. At the outset, historical milestones of exercise science literature are summarized. It is followed by details about the currently available regulations that help to reduce the risk of violating good scientific practices. We also outline the unique characteristics of sports-related research with a narrative of the major differences between sports and drug-based trials. An emphasis is then placed on the importance of well-designed studies to improve the interpretability of results and generalizability of the findings. This review finally suggests that sports researchers should comply with the available guidelines to improve the planning and conduct of future research thereby reducing the risk of harm to research participants. The authors suggest creating an oath to prevent malpractice, thereby improving the knowledge standards in sports research. This will also aid in deriving more meaningful implications for future research based on high-quality, ethically sound evidence.

1. Introduction

Historical milestones of ethical and scientific misconduct in research.

Until the early 19th century, ‘truth’ was fundamentally influenced by cults, religion, and monarchism [ 1 ]. With the ‘enlightenment’ of academicians, clinicians and researchers in the 19th century [ 2 ], scientific research started to impact the lives of people by providing balanced facts, figures and uncertainties, thereby leading to a better explanation for reality (i.e., evidence vs. eminence). However, dualistic thinking was still interfering with the newer rationalized approach as the estimation of reality by scientific estimation was still being challenged by the dogmatic view of real truth [ 3 ].

Over the last decades, researchers underestimated the importance of good ethical conduct [ 4 ] in human research by misinterpreting the probabilistic nature of scientific reasoning. Scientific research had constantly been exploited for personal reputations, political power, and terror [ 3 ]. The ‘Eugenics program’ originating from the Nazi ideology is an unsettling example of ethical failure and scientific collapse. As part of this program, scientific research was being exploited to justify unwanted sterilization (0.5 million) [ 5 ] and mass-killing (0.25 million) [ 6 ] for the sake of selection and elimination of ‘unfit genetic material’. In 1955, more than 200,000 children were infected with a Polio vaccine that was not appropriately handled as per the recommended routines [ 7 ]. Likewise, the thalidomide disaster of 1962 led to limb deformities and teratogenesis in more than ten thousand newborn children [ 8 ]. Considering the aforementioned unethical practices and misconduct, there is a strong need to comply with and re-emphasize the importance of ethics and good scientific practice in humans and other species alike.

In the process of evolution of scientific research, the Nuremberg code laid the foundation for developing ethical biomedical research principles (e.g., the importance of ‘voluntary and informed consent’) [ 9 ]. Based on the Nuremberg code and the previously available medical literature, the first ethical principles (i.e., Declaration of Helsinki) were put into practice for safe human experimentation by the World Medical Association in 1964. This declaration proved to be a cornerstone of medical research involving humans and emphasized on considering the health of the patients as the topmost priority [ 10 ]. The year 1979 could also be seen as an important milestone, as the ‘Belmont report’ was introduced that supported the idea: ‘the interventions and drugs have to eventually show beneficial effects’. The Belmont report suggests that the recruitment, selection and treatment of participants needs to be equitable. It also highlights the importance of providing a valid rationale for testing procedures to prevent and minimize the risks or harms to the included participants [ 11 ].

As a result of the introduction of ethical principles, it became evident that research designs and results should be independent of political influence and reputational gains. There should also be no undeclared conflicts of interest [ 12 ]. Interestingly, sports and exercise science emerged as politically meaningful instruments for showing power during the Cold War (i.e., Eastern socialism versus Western capitalism) [ 13 ]. Researchers were either being manipulated or sometimes not even published to reduce awareness about the negative effects of performance-enhancing substances [ 14 , 15 ]. Even though these malpractices were strictly against the principles of the Declaration of Helsinki [ 14 ], these were prevalent globally, thereby contributing to several incidents of doping in sports [ 16 ]. To further minimize unethical research practices, the Good Clinical Practice (GCP) Standards were presented in 1997 to guide the design of clinical trials and formulation of valid research questions [ 17 ]. However, some authors criticise the Good Clinical Practice standards as not being morally sufficient to rule out personal conflicts of interest when compared to the ethical standards of the Declaration of Helsinki [ 18 ].

Nowadays, professional development and scientific reputation in the research community are related to an increase in the number of publications in high-ranked journals. However, the increasing number of publications gives very little information about the scientific quality of the employed methods, as some of the published papers either contain manipulated results [ 19 ] or methods that could not be replicated [ 12 ]. Moral and ethical standards are widely followed by sports researchers as evidenced by the applied methods that are mostly safe, justified, valuable, reliable and ethically approved. However, the ethical approval procedures, the dose and the application of exercise training vary greatly between studies and institutions. The review by Kruk et al., 2013 [ 20 ] provides a balanced summary of the various principles based on the Nuremberg Code and the Declaration of Helsinki. GCP standards of blinding (subjects and outcome assessors), randomization, and selection are not consistently considered and are sometimes difficult to follow due to limited financial and organizational resources. There is a prevalent trend in the publication of positive results in the scientific community, as negative results often fail to pass editorial review [ 21 ]. Additionally, certain unethical research practices have been observed, such as the multiple publication of data from a single trial (referred to as “data slicing”), the submission of duplicate findings to multiple journals, and instances of plagiarism [ 22 ]. These limitations negatively affect the power, validity, interpretability and applicability of the available evidence for future research in sports and exercise science. Previous research showed that, if used systematically, lifestyle change and exercise interventions can prove to be one of the most efficient strategies for obtaining positive health outcomes [ 23 ] and longevity [ 24 ]. Hence, the present article recommends avoiding malpractices and using the underlying ethical standards to balance risks and benefits along with preventing data manipulation and portrayal of false-positive results.

2. Codes of Conduct in Sport Research

All the available codes, declarations, statements, and guidelines aim at providing frameworks for conducting ethical research across disciplines. These frameworks generally cover the regulative, punitive, and educational aspects of research. Codes of ethical conduct not only outline the rules and recommendations for conducting research but also outline punishments in case of non-compliance or misconduct. Hence, these ethical codes and guidelines should be considered the most important educational keystones for researchers as these frameworks allow scientists to design and conduct their studies in a better way. Declarations and guidelines are regularly updated to accommodate newer information and corrections. Thus, one also needs to be flexible when using these guidelines as these reflect ongoing scientific and societal development.

Codes and declarations in sport and exercise science regulate both quantitative and qualitative research and include information about human and animal rights, research design and integrity, authorship and plagiarism. We will categorize these guidelines based on the individuals whom guidelines aim to protect (e.g., participants or researchers).

Legal codes and norms of a country are inherently binding to the researchers and institutions who are conducting the research and do not require ratification from the researching individual or organization. These laws can include data storage, child protection, intellectual property rights, or medical regulations applicable to a specific study. However, ethics codes not only cater to the questions of legality but also include moral parameters of research like conducting ‘true’ research. Likewise, if the codes are drafted by a research organization, everyone conducting research for this particular organization is supposed to follow these codes.

Researchers have the responsibility to assess which codes, and standards are relevant to their field of research depending on the country, participants, and research institution ( Table 1 ). This can be confirmed by the academic supervisors or the scientific ethics board of the research institution. While there is a growing number of codes and guidelines for different research fields, it is important to consider that none of these can cater to the needs of every single research design alone. For example, the Code of Ethics of the American Sociological Association (ASA) states: “Most of the Ethical Standards are written broadly in order to apply to sociologists in varied roles, and the application of an Ethical Standard may vary depending on the context” [ 25 ]. Hence, as ethical standards are not exhaustive, scientific conduct that is not specifically addressed by this Code of Ethics is not necessarily ethical or unethical [ 25 ].

Detailed overview of Codes, Declarations, Statements and Guidelines relevant for sports and exercise science research.

It is crucial to recognize the purpose of an ethics code rather than just following it for ticking boxes. Understanding the aims and limitations of an ethics code will allow for a more meaningful application of the underlying principles to the specific context without ignoring the potential limitations of a study. Unintentional transgressions can occur through subconscious bias, fallacies, or human errors. However, the unintentional errors can be mitigated by following the streamlined process of research conception, method development and study conduct following approval from the Institutional Review Boards (IRBs), Ethical Research Commissions (ERCs), supervisors, and peers. In case of intentional errors, the punitive aspect needs to come into action and the transgressors might need to be investigated and sanctioned, either by the research organizations or by law.

3. Differences between Drug and Exercise Trials

Randomized controlled trials (RCTs) are regarded as the highest level of evidence [ 26 , 27 ]. For both the cases (exercise vs. drug studies), RCTs primarily aim at investigating the dose-response relationships and obtaining causal relationships [ 28 ]. Drug trials compare one drug to other alternatives (e.g., another drug, a placebo, or a treatment as usual). Likewise, exercise trials often compare one mode of exercise to another exercise or no exercise interventions (e.g., usual care, waitlist control, true control, etc.), ideally under caloric, workload or time-matched conditions. However, placebo or sham trials are still rare in sports and exercise research due to their challenging nature [ 29 ]. The following quality requirements should be fulfilled for conducting high-quality exercise trials: (a) ensure blinding of assessors, participants and researchers; (b) placebo/sham intervention (if possible), and (c) adequate randomization and concealed allocation.

3.1. Blinding

The term ‘blinding’ (or ‘masking’) involves keeping several involved key persons unaware of the group allocation, the treatment, or the hypothesis of a clinical trial [ 30 , 31 , 32 , 33 , 34 ]. The term blinding and also the types of blinding (single, double, or triple blind) are being increasingly used and accepted by researchers but there is a lack of clarity and consistency in the interpretation of those terms [ 33 , 35 , 36 ]. Blinding should be conducted for participants, health care providers, coaches, outcome assessors, data analysts, etc. [ 31 , 33 , 34 , 37 ]. The blinding process helps in preventing bias due to differential treatment perceptions and expectations of the involved groups [ 28 , 30 , 31 , 32 , 38 , 39 , 40 ].

Previous research has shown that trials with inadequately reported methods [ 41 ] and non-blinded assessors [ 42 ] or participants [ 43 ] tend to overestimate the effects of intervention. Hence, blinding serves as an important prerequisite for controlling the methodological quality of a clinical trial, thereby reducing bias in assessed outcomes. Owing to this reason, most of the current methodological quality assessment tools and reporting checklists have dedicated sections for ‘blinding’. For example, three out of eleven items are meant for assessing ‘blinding’ in the PEDro scale [ 44 ]; the CONSORT checklist for improving the reporting of RCTs also includes a section on ‘blinding’ [ 45 ]. In an ideal trial, all participants involved in the study should be ‘blinded’ [ 30 ]. However, choosing whom to ‘blind’ also depends on and varies with the research question, study design and the research field under consideration. In the case of exercise trials, blinding is either not adequately done or poorly reported [ 36 , 46 ]. The lack of reporting might be the result of a lack of awareness of the blinding procedures rather than the poor methodological conduct of the trial itself [ 34 ]. Hence, blinding is not sufficiently addressed in exercise, medicine and psychology trials [ 47 , 48 ] due to lacking knowledge, awareness and guidance in these scientific fields leading to an increased risk of bias [ 48 ].

Blinding of participants is difficult to achieve and maintain [ 34 , 39 , 40 , 49 ] in exercise trials as the participants would usually be aware of whether they are in the exercise group or the control (inactive) group [ 31 , 39 , 50 ]. Likewise, the therapists are also generally aware of the interventions they are delivering [ 51 ], and the assessors are aware of the group allocation because it is common in sports sciences that researchers are involved in different parts of research (recruiting, assessment, allocation, training, data handling analysis) due to limited financial resources. Thus, the adequacy of blinding is usually not assessed as it is often seen as ’impossible’ in exercise trials.

Consequently, we strongly recommend using independent staff for testing, training, control and supervision to improve possibilities of blinding of the individuals involved in the study [ 39 ]. Researcher also need to decide if it is methodologically feasible and ethically acceptable to withhold the information about the hypothesis and the study aims [ 52 ] from assessors and participants. This needs to be considered, addressed and justified before the trial commences (i.e., a priori). While reporting methods of exercise trials, it is important not only to describe who was blinded but also to elaborate the methods used for blinding [ 33 , 48 ]. This helps the readers and research community to effectively evaluate the level of blinding in the trial under consideration [ 33 , 53 ]. Furthermore, if blinding was carried out, the authors can also include the assessment of success of the blinding procedure [ 33 , 54 ]. Readers can access more information about the various possibilities for blinding using the following link ( http://links.lww.com/PHM/A246 accessed on 10 October 2022) [ 36 ].

3.2. “Placebo” (or Sham Intervention)

‘Placebo’ is an important research instrument used in pharmacology trials to demonstrate the true efficacy of a drug by minimizing therapy expectations of the participants [ 55 ]. As the term placebo is generally used in a broad manner, precise definitions are difficult. Placebo is used as a control therapy in clinical trials owing to their comparable appearance to the ‘real’ treatment without the specific therapeutic activity [ 56 ]. In an ideal research experiment, it would not be possible to differentiate between a placebo and an intervention treatment [ 57 , 58 ]. The participants should not be aware of the treatment group either, because it can lead to the knowledge of whether they received a placebo or the investigated drug [ 57 ]. A review of clinical trials comparing ‘no treatment’ to a ‘placebo treatment’ concluded that the placebo treatment had no significant additional effects overall but may produce relevant clinical effects on an individual level [ 59 ]. As outlined previously, the placebo effect is rarely investigated in sports and exercise studies. It is generally investigated using nutritional supplements, ergonomic aids, or various forms of therapy in the few existing studies [ 60 ]. Placebos have been shown to have a favorable effect on sports performance research [ 61 ], implying that these could be used for improving performance without using any additional performance-enhancing drugs [ 62 ].

However, it is quite difficult to have an adequate placebo in exercise intervention studies, as there is currently no standard placebo for structured exercise training [ 28 ]. For exercise training interventions, a placebo condition is defined as “an intervention that was not generally recognized as efficacious, that lacked adequate evidence for efficacy, and that has no direct pharmacological, biochemical, or physical mechanism of action according to the current standard of knowledge” [ 63 ]. As a result, using a placebo in exercise interventions is often seen as impractical and inefficient [ 57 , 58 ]. As the concept of blinding is also linked to the use of a placebo, it is usually difficult to implement in exercise trials.

When it comes to exercise experiments, an active control group is considered to be more effective than a placebo group [ 10 , 28 ]. In other cases, usual care or standard care can also be used as the control intervention [ 28 ]. In exercise trials, instead of using the term ‘placebo treatment’, the terms “placebo-like treatment” or “sham interventions” should be applied [ 64 , 65 ]. Previous recommendations by other researchers [ 61 ] also underpin our rationale.

3.3. Randomization and Allocation Concealment

Group allocation in a research study should be randomized and concealed by an independent researcher to minimize selection bias [ 66 ]. Randomization procedures ensure that the differences in treatment outcomes solely occur by chance [ 28 , 67 ]. Several methods for randomization are available; however, methods such as stratified randomization are being increasingly popular as they ensure equal distribution of participants to the different groups based on several important characteristics [ 66 ]. Other types of randomization, such as cluster randomization, may be appropriate when investigating larger groups, for example, in multicenter trials [ 28 ].

Since researchers are frequently involved in all phases of a trial (recruitment, allocation, assessment and data processing), randomization should usually be conducted by someone who is not familiar with the project’s aims and hypotheses. In studies with a large number of participants, the interaction between subjects and assessors can significantly impact the results [ 68 ]. The randomization procedure used in the clinical trial should be presented in scientific articles and project reports so that readers can understand and replicate the process if needed [ 66 ]. Based on the aforementioned aspects, exercise trials are not easily comparable to drug trials and the differences lead to difficulties in conducting scientifically conceptualized exercise trials. However, researchers should strive for quality research by using robust methods and providing detailed information on blinding, randomization, choice of control groups, or sham therapies, as appropriate. Researchers should critically evaluate the risk-benefit ratio of exercise so that the positive impacts of exercise on health can be derived and the cardiovascular risks associated with exercise could be minimized [ 69 ].

4. Key Elements of an Ethical Approval in Exercise Science

As previously described, ethical guidelines are needed to protect study participants from potential study risks and increase the chances of attaining results that ease interpretation. Therefore, a prospective ethical approval process is required prior to the recruitment of the participants [ 70 ]. This practice equally benefits the participants by safeguarding them against potential risks and the practitioners who base their clinical decisions on research results. Research results from a study with a strong methodology will enable informed and evidence-based decision making. If the methodology of a research project contains some major flaws, it will negatively affect the practical applicability of the observed results [ 71 ]. Various journal reviewers provide suggestions to reject manuscripts without any option to resubmit if no ethical approval information is provided. This demonstrates the importance of ethical approval and proper scientific conduct in research [ 70 ].

The following key elements need to be addressed in an ethical review proposal: Introduction, method, participant protection, and appendix. These key elements should be detailed in a proposal with at least three crucial characteristics addressed in each section ( Figure 1 ). This hands-on framework would help to expedite the process of decision-making for members of the ethics committee [ 72 ].

Overview 4 × 3 short list for outlining ethical approval in sport and exercise science.

The ‘introduction’ section should start with a general overview of the current state of research [ 4 ]. Researchers need to describe the rationale of the proposed study in an easy and comprehensible language considering the current state of knowledge on that topic [ 4 ]. The description helps to provide a balanced summary of the risks and benefits associated with the interventions in the proposed study. The novelty of the stated research question and the underlying hypothesis must be justified. If the proposed study fails to expand the current literature on the topic under consideration, conducting the study would be a ‘waste’ of time and financial resources for researchers, participants, and funding agencies [ 73 ]. Hence, ethical approvals should not be given for research projects that fail to provide novelty in the approach to the respective research area. The introduction should also include information on funding sources including the name of the funding partner, duration of monetary/resource support, and any potential conflicts of interest. If no funding is available, authors should declare that ‘This study received no funding’ [ 70 ].

The subsequent ‘methods’ section should include detailed information about the temporal and structural aspects of the study design. Researchers should justify the used study design in a detailed manner [ 4 , 28 ]. Multiple research designs can be utilized for addressing a specific research question, including experimental, quasi-experimental, and single-case trial designs [ 74 , 75 ]. However, a valid rationale should be provided for choosing a randomized cross-over trial design when the gold standard of randomized control trials is also feasible. Readers are advised to refer to the framework laid down by Hecksteden et al., 2018, for extensive information on this section [ 28 ]. Researchers should also provide a broad, global and up-to-date literature-based justification for their interventions or methods employed in the study. For instance, if the participants are asked to consume supplements, the recommendations for the dose needs to be explained based on prior high-quality studies and reviews for that supplement [ 4 ]. The criteria for subject selection (inclusion and exclusion criteria) and sample size estimation need to be explained in detail to allow replication of the study in the future [ 76 ]. Lacking sample size estimations is only acceptable in rare cases and requires detailed explanations (e.g., pilot trials, exploratory trials to formulate a hypothesis, acceptability trials). Moreover, sufficient details should be provided for the measuring devices used in the study and a sound rationale should be provided for the choice of that particular measuring device and the measured parameters [ 4 ].

The section on ‘participant protection’ deals with potential risks (physical and psychological adverse outcomes) and benefits to the participants. The focus should be adjusted to the study population under consideration. For example, while conducting a study on a novel weight training protocol with elite athletes, all information and possible effects on the athletes’ performance need to be considered, as their performance level is their ‘human capital’ [ 4 ]. The investigators also need to provide information on the individuals responsible for different parts of the study, i.e., treatment provider, outcome assessor, statistician, etc. In some cases, externally qualified personnel are needed during the examination process. For example, a physician might be needed for blood sampling or biopsies and this person should also be familiar with the regulations and procedures to avoid risk to the participants due to a lack of experience in this area. Prior experience and qualifications are required for conducting research with vulnerable groups, such as children, the elderly and pregnant females. Williams et al. (2011) summarized essential aspects of conducting research studies with younger participants [ 77 ]. Overall, the personnel should be blinded to the details of the group allocation and participants, if possible [ 30 ]. The study applicants also need to provide information about the planned compensation and the follow-up interventions. Harriss and colleagues suggested that the investigators are not expected to offer the treatments in case of injury to the participants during the study (except first aid) [ 70 ]. However, this recommendation is not usually documented and translated into research practice.

The ‘appendix’ section should contain relevant details about the following: consent, information to the participants and a declaration of pre-registration. The information to the participant and the consent forms need to be documented in an easy to understand language. A brief summary of the purpose of the study and the tasks to be performed by the participants should also be added. Then, a concise but comprehensive overview of the potential risks and benefits is needed. The next section should include information for participants: the participants’ right to decline participation without any consequence and the right to withdraw their consent at any time without any explanation. The regulations for the storage, sharing and retention of study data need to be detailed [ 70 ]. The names and institutional affiliations of all the researchers along with the contact information of the project manager should be listed. A brief overview of the study’s aim, tasks, methods and data acquisition strategies should be described. Finally, consent is needed for processing the recorded personal data [ 70 ]. The last section of the ‘appendix’ must include a declaration of pre-registration (e.g., registration in the Open Science Framework or trial registries) to avoid alterations in the procedure afterward and facilitate replication of study methods [ 78 ].

5. Study Design and Analysis Models

The process of conceptualizing an exercise trial might involve various pitfalls at every stage (hypothesis formulation, study design, methodology, data acquisition, data processing, statistical analysis, presentation and interpretation of results, etc.). Thus, the entire ‘design package’ needs to be considered when constructing an exercise (training) trial [ 28 ]. Formulation of an adequate and justified research question is the essential aspect before starting any research study. Formulating a good research question is pivotal to achieve adequate study quality [ 79 ]. According to Banerjee et al., 2009 [ 80 ], “a strong hypothesis serves the purpose of answering major part of the research question even before the study starts”. As outlined in previous sections, ethical research aspects must be taken into account while framing the research question to protect the privacy and reduce risks to the participants. The confidentiality of data should be ascertained and the participants should be free to withdraw from the study at any time. The authors should also avoid deceptive research practices [ 79 ].

Hecksteden et al., 2018, suggested that RCTs can be regarded as the gold standard for investigating the causal relationships in exercise trials [ 28 ]. However, it is sometimes not feasible to conduct RCTs in the field of sports science due to logistical issues, such as smaller sample sizes and blinding the location of the study (e.g., schools, colleges, clinics, etc.). In this case, alternative study designs such as cluster-RCTs, randomized crossover trials, N-of-1 trials, uncontrolled/non-randomized trials, and prospective cohort studies can be considered [ 81 ]. Considering the complex nature of exercise interventions, the Consensus on Exercise Reporting Template (CERT) has been developed to supplement the reporting and documentation of randomized exercise trials [ 81 ]. Adherence to these templates might help to improve the ethical proposal reporting standards when designing new RCTs.

A recent comment, in the journal ‘Nature’, highlights the importance of using the right statistical test and properly interpreting the results. According to the paper, the results of 51 percent of articles published in five peer-reviewed journals were misinterpreted [ 82 ]. Frequentist statistics and p -values are popular summaries of experimental results but there is a scope for misinterpretation due to the lack of supplementary information with these statistics. For instance, authors tend to draw inferences about the results of a study based on certain ‘ threshold p-values ’ (generally p < 0.05) [ 83 ]. However, with an increase in sample size, the p -value tends to come closer to zero regardless of the effect size of the intervention [ 83 ]. With the rise of larger datasets and thus potentially higher sample sizes, the p -value threshold becomes questionable. A call for action has recently been raised by more than 800 signatories to retire statistical significance and to stop categorizing results as being statistically significant or non-significant. Recently, researchers suggested using confidence intervals for improving the interpretation of study results [ 82 ]. Although alternative methods such as magnitude-based inference (MBI) exists, there is scarce evidence that MBI has checked the use of p -value and hypothesis testing by sports researchers [ 84 ]. MBI tends to reduce the type II error rate but it increases the type I error rate by about two to six times the rate of standard hypothesis testing [ 85 ]. In the next paragraphs, we focus on the commonly used practices within the frequentist statistics domain.

Frequentist statistical tests are categorized into parametric and non-parametric tests. Non-parametric tests do not require the data to be normally distributed, whereas parametric tests do [ 86 ]. The following factors help in deciding the appropriate statistical test: (a) type of dependent and independent variables (continuous, discrete, or ordinal); (b) type of distribution, if the groups are independent or matched; (c) levels of observations; and (d) time dependence. Readers can choose the right statistical tests based on the type of research data they are planning to use [ 87 , 88 ]. A recent publication outlined 25 common misinterpretations concerning p -values, confidence intervals, power calculations and key considerations while interpreting frequentist statistics [ 89 ]. We recommend sports researchers consider the listed warnings while interpreting the results of statistical tests.

Out of the various frequentist statistical methods, analysis of variances (ANOVA) is one of the most widely used tests to analyze the results of RCTs. It does not, however, provide an estimate of the difference between groups, which is usually the most important aspect of an RCT [ 90 ]. Linear models (e.g., t -tests) suffer from similar issues when analyzing categorical variables, which are a wider part of RCT analysis [ 91 ]. Type I errors (false positive, rejecting a null hypothesis that is correct) and Type II errors (false negative, failure to reject a false null hypothesis) are often discussed while interpreting RCT results [ 80 ]. Though it is not possible to completely eliminate these errors, there are ways to minimize their likelihood and report the statistics appropriately. The most commonly used methods for minimizing error rates include the following: (a) increasing the sample size; (b) adjusting for covariates and baseline differences [ 92 ]; (c) eliminating significance testing; and (d) reporting a confusion matrix [ 80 , 86 , 93 ].

Mixed logit models are potential solutions for some of the challenges listed above. They combine the advantages of random effects logistic regression analysis with the benefits of regression models [ 94 ]. In addition, mixed logit models, as part of the larger framework of generalized linear mixed models, provide a viable alternative for analyzing a wide range of outcomes. For increasing the transparency and interpretability of the observed results, mixed logit classification algorithms and evaluation matrices such as cross validation and presentation of a confusion matrix (type I and type II error rates) can be utilized [ 86 ]. Mixed logit models can also be utilized as predictive models rather just ‘inference testing’ models.

6. Limitations

Despite extensive efforts to incorporate empirical and current evidence regarding good scientific practice and ethics into this paper, it is possible that some literature may have been omitted. Nonetheless, the paper comprehensively covers key aspects of prevalent ethical misconducts and the standards that should be upheld to prevent such practices. As a result, readers can have confidence in the literature presented, which is based on a substantial body of existing evidence. Readers are also encouraged to engage in critical evaluation and to consider new approaches that could improve the overall scientific literature.

7. Conclusions

We highlighted the various pitfalls and misconduct that can take place in sports and exercise research. Individual researchers associated with a research organization need to comply with the highest available standards. They need to maintain an intact ‘moral compass’ that is unaffected by expectations and environmental constraints thereby reducing the likelihood of unethical behavior for the sake of publication quantity, interpretability, applicability and societal trust in evidence-based decision-making. To achieve these objectives, a Health and Exercise Research Oath (HERO) could be developed that minimizes the allurement to cheat and could be used by PhD candidates, senior researchers, and professors. Such an oath would prevent intentional or unintentional malpractices in sport and exercise research, thereby strengthening the knowledge standards based on ethical exercise science research. Overall, this will also improve the applicability and interpretability of research outcomes.

Acknowledgments

We acknowledge the financial support of the German Research Foundation (DFG) and the Open Access Publication Fund of Bielefeld University for the article processing charge.

Funding Statement

This research received no external funding.

Author Contributions

Conceptualization, N.K.A., G.R., S.C., A.P., B.K.L., A.N., P.W. and L.D.; methodology, N.K.A., G.R., S.C., A.P., B.K.L., A.N., P.W. and L.D.; resources, P.W. and L.D.; data curation, N.K.A., G.R., S.C., A.P., B.K.L., A.N., P.W. and L.D.; writing—original draft preparation, N.K.A., G.R., S.C., A.P., B.K.L., A.N., P.W. and L.D.; writing—review and editing, N.K.A., G.R., S.C., A.P., B.K.L., A.N., P.W. and L.D.; visualization, N.K.A., G.R., S.C., A.P., B.K.L., A.N., P.W. and L.D.; supervision, P.W. and L.D.; project administration, L.D. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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