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A century of exercise physiology: key concepts in …

  • Published: 17 December 2021
  • Volume 122 , pages 1–4, ( 2022 )
  • Michael I. Lindinger   ORCID: orcid.org/0000-0003-1001-4302 1 &
  • Susan A. Ward 2  

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The Editorial Board of the European Journal of Applied Physiology has endorsed a topical series in the theme “A Century of Exercise Physiology”. History tells us that the importance of exercise in healthful living goes back to antiquity: Susruta (ca. 600 B.C.) in India, Hippocrates (460–370 B.C.) in Greece and Galen (129–210 A.D.) in Rome (Berryman 2010 ; Shephard 2013 ; Tipton 2014 ). The Eighteenth Century saw exercise being promoted as a medical intervention, as exemplified by the London physician Francis Fuller who in 1705 published “Medicina Gymnastica or A Treatise Concerning the Power of Exercise, with Respect to the Animal Oeconomy; and the Great Necessity of it in the Cure of Several Distempers”(Fuller 1705 ). However these recognitions of the importance and power of exercise do not mean that the physiological concepts underpinning present-day understanding of exercise were understood at that time, or even recognized. It was only during the past 300 years that important advances in understanding were made using the scientific methods of experimentation, observation, careful recording of data, logical interpretation and inference, and the publication of results. These practices facilitated, if not dictated, the development of new theories and concepts in exercise physiology.

The idea for this series comes from groupings of seminal research papers published in the first three decades of the Twentieth Century that established the foundations of modern exercise physiology. On reviewing a hundred or so of these papers, several notable features arise. First, exercise physiology was a hot research topic then, and it has continued to be. Second, many of the key journals publishing the work of these pioneering exercise physiologists have consistently published in this area for more than a century, such as: American Journal of Physiology, Journal of Biological Chemistry, Journal of Physiology, Plügers Archiv (later becoming European Journal of Physiology) and Skandinavisches Archiv für Physiologie (later becoming Acta Physiologica Scandinavica and then Acta Physiologica). The European Journal of Applied Physiology came into being on Feb. 1, 1928 as Arbeitsphysiologie, with the first volume comprising five papers focusing on exercise and occupational physiology.

Third, many of the experiments performed by these early researchers were creatively and rigorously designed and executed, with these designs laying a foundation for work that followed. Fourth, a number of conclusions of these studies have been supported over the passage of time. Noteworthy too, however, is that some of the unsupported conclusions are still accepted as ‘true’ by many in the exercise and sports physiology domain, of which perhaps one of the more striking examples is the assertion that “lactic acid causes fatigue” in human subjects performing exercise (Jervell 1928 ). And fifth, a number of conclusions of these studies have NOT been supported with the passage of time.

The choice of the initial three decades of the Twentieth Century as the period within which to anchor the ‘key concepts in exercise physiology’ series is not arbitrary. This is a period of time that allowed for the flourishing of many disciplines of science, human physiology included. And perhaps especially human physiology, given the demands of warfare and the necessary sequelae of medical treatment and therapies aimed at functional recovery, such as Pilates (summarized later by Pilates 1945 ). Influential publications accrued from key pioneers in the discipline of exercise physiology, with August Krogh and Archibald Vivian Hill each being awarded the Nobel Prize in Physiology or Medicine (in 1920 and 1922, respectively). One can point to:

1) John Scott Haldane and Claude Gordon Douglas (Oxford University) who had a productive collaboration in the early Twentieth Century that focused on ventilatory control and pulmonary gas exchange. For example, they concluded in 1909 that the hyperpnea during moderate exercise was mediated by a rise in PCO 2 in the respiratory centers (Haldane and Priestley 1905 ), also suggesting that it was slow in onset (Douglas and Haldane 1909 ). Douglas would later report a close association between ventilation and CO 2 output during exercise (Douglas 1927 ), which is now one of the accepted tenets of exercise physiology.

2) Almost contemporaneously, August Krogh and Johannes Lindhard (University of Copenhagen) would present results at odds with those of the Oxford investigators, documenting an immediate hyperpnea at exercise onset which they ascribed to cortical irradiation, a precursor of what is now known as central command (Krogh and Lindhard 1913a ). They were also at odds with regard to whether the physiological dead space increased during exercise (Douglas and Haldane 1912 ) or remained unchanged (Krogh and Lindhard 1913b ); it is now widely recognized to increase, but less so than tidal volume such that the dead space to tidal volume ratio decreases. But it is Krogh’s work on the role of muscle capillary recruitment during exercise in supporting tissue oxygen delivery that is most noteworthy and for which he was awarded his Nobel Prize (Krogh 1919a , b , c ).

3) In 1923, David Barr and Harold Himwich (Cornell University) provided the first comprehensive description of arterial and venous blood acid–base status during moderate and high-intensity exercise in the Journal of Biological Chemistry “Studies in the physiology of muscular exercise” series (Barr et al. 1923 ; Barr and Himwich 1923a , b ; Barr 1923 ; Himwich and Barr 1923 ). This was timely, given the limitations of using alveolar gas to infer arterial blood PCO 2 in the earlier Oxford and Copenhagen investigations.

4) It was also in the 1910s and 1920s that the analysis of heat production in isolated frog muscle by Archibald Vivian Hill (University College London) pioneered muscle metabolic mechanisms and muscle mechanics, thus opening the way to research investigating effects in different types of muscle fibers. Hill’s work, together with the biochemical analyses of his Nobel co-Laureate Otto Meyerhof, led to the recognition of distinct aerobic and anaerobic metabolic mechanisms in exercising muscle (Hill and Meyerhof 1923 ). These principles were applied to exercising humans, leading to the concepts of a maximum O 2 uptake and an oxygen debt comprising a fast component reflecting intramuscular oxidative conversion of lactate to glycogen and a slower component reflecting delayed oxidation of lactate that had diffused out of the exercised muscle (Hill and Lupton 1923 ).

And 5) In 1927 Harvard University’s Harvard Fatigue Laboratory was established with Lawrence J Henderson as its titular Head but under the scientific leadership of D. Bruce Dill. Over the next two decades, the Laboratory would prove to an influential international force in many areas of exercise physiology (Tipton and Folk 2014 ). Dill’s work over five decades set a standard for integrative investigation that began with the impressive series “Studies in muscular activity” (Bock et al. 1928a , b , c , 1932 ; Talbott et al. 1928 ; Dill and Fölling 1928 ; Dill et al. 1930 ) covering areas such as cardiorespiratory physiology, pulmonary gas exchange and metabolism. Of particular significance at the start of the 1930s was the revisionist evaluation of the Hill-Meyerhof concept by Margaria, Edwards and Dill (Margaria et al. 1933 ): the fast (alactic) component being ascribed to phosphocreatine resynthesis and therefore independent of lactate oxidation.

There are numerous other contributions dating from this period, deserving of mention being those of Francis Benedict and Edward Cathcart (Benedict and Cathcart 1913 ), Francis Bainbridge (Bainbridge 1919 ), Joseph Barcroft (Barcroft 1934 ) and Yandell Henderson (Henderson 1923 ).

The collective body of work of these investigators fueled the legitimizing of exercise physiology, both basic and applied, as an important area of research and study in its own right. But it would not be until the 1960s—nearly 40 years after the founding of the Harvard Fatigue Laboratory—that the first academic departments of exercise physiology would come into existence, exercise physiology previously having been largely subsumed within physical education departments. As a result, we are now in an era where the importance of exercise physiology in athletic achievement, physical and mental training, wellness and healthy living, injury recovery and post-trauma recovery therapies is to all intents universally recognized. Regular exercise is foundational to human health, both mental and physical (Booth et al. 2000 ).

In the present Century of Exercise Physiology Series the authors have set out to re-examine foundational research papers published between 1909 and 1930 and take the reader on a tour through the historical development of mechanisms contributing to our current understanding of exercise physiology. Each review highlights conclusions that have been supported and those that have not been supported over the passage of time. The key research driving increased understanding of function is highlighted, decade by decade, to build the story of our current understanding. And yes, there remain critical knowledge gaps and areas of controversy that underpin research efforts in hundreds of exercise physiology labs around the world. The papers in the series are not a historical step-by-step review of the literature. The focus is on the key concepts, and how these are linked together to bring us to our current state-of-the-science. The focus is on physiological mechanisms, not history.

In this issue of the Journal we present the first paper in the Century of Exercise Physiology Series. David Poole has taken on the task of developing our understanding of muscle oxygenation (Poole et al. 2021 ). The following issues will contain one or two reviews written by senior researchers whose work has spanned a significant portion of the past century. These are people who, through their published work, have embraced the historical foundations of their research area to guide their research progress.

As the series unfolds you may find that there are gaps. We therefore also invite you, the reader, to consider contributing to this series.

Mike Lindinger

EJAP Reviews Editor

Former EJAP Editor-in-Chief (2007–2012)

Human Bio-Energetics Research Centre, Crickhowell, Wales, NP8 1AT.

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Lindinger, M.I., Ward, S.A. A century of exercise physiology: key concepts in …. Eur J Appl Physiol 122 , 1–4 (2022). https://doi.org/10.1007/s00421-021-04873-4

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Issue Date : January 2022

DOI : https://doi.org/10.1007/s00421-021-04873-4

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  • v.8(7); 2018 Jul

Health Benefits of Exercise

Gregory n. ruegsegger.

1 Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211

Frank W. Booth

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

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.

The aim of this introduction is briefly to document facts that health benefits of physical activity predate its readers. In the 5th century BC, the ancient physician Hippocrates stated: “All parts of the body, if used in moderation and exercised in labors to which each is accustomed, become thereby healthy and well developed and age slowly; but if they are unused and left idle, they become liable to disease, defective in growth and age quickly.” However, by the 21st century, the belief in the value of exercise for health has faded so considerably, the lack of exercise now presents a major public health problem ( Fig. 1 ) ( Booth et al. 2012 ). Similarly, the lack of exercise was classified as an actual cause of chronic diseases and death ( Mokdad et al. 2004 ).

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Simplistic overview of how physical activity can prevent the development of type 2 diabetes and one of its complications, cardiovascular disease. Physical inactivity is an actual cause of type 2 diabetes, cardiovascular disease, and tens of other chronic conditions ( Table 1 ) via interaction with other factors (e.g., age, diet, gender, and genetics) to increase disease risk factors. This leads to chronic disease, reduced quality of life, and premature death. However, physical activity can prevent and, in some cases, treat disease progression associated with physical inactivity and other genetic and environmental factors.

Published in 1953, Jeremy N. Morris and colleagues conducted the first rigorous epidemiological study investigating physical activity and chronic disease risk, in which coronary heart disease (CHD) rates were increased in physically inactive bus drivers versus active conductors ( Morris et al. 1953 ). Since this pioneering report, a plethora of evidence shows that physical inactivity is associated with the development of 40 chronic diseases ( Table 1 ), including major noncommunicable diseases such as type 2 diabetes (T2D) and CHD, and as premature mortality ( Booth et al. 2012 ).

Worsening of 40 conditions caused by the lack of physical activity with growth, maturation, and aging throughout life span

The breadth of the list implies that a single molecular target will not substitute for appropriate daily physical activity to prevent the loss of all listed items.

In this review, we highlight the far-reaching health benefits of physical activity. However, note that the studies cited here represent only a fraction of the >100,000 studies showing positive associations between the terms “exercise” and “health.” In addition, we discuss how exercise promotes complex integrative responses that lead to multisystem responses to exercise, an underappreciated area of medical research. Finally, we consider how strategies that “mimic” parts of exercise training compare with physical exercise for their potential to combat metabolic disease.

EXERCISE IMPROVES CARDIORESPIRATORY FITNESS

There is arguably no measure more important for health than cardiorespiratory fitness (CRF) (commonly measured by maximal oxygen uptake, VO 2max ) ( Blair et al. 1989 ). For example, Myers et al. (2002 ) showed that each 1 metabolic equivalent (1 MET) increase in exercise-test performance conferred a 12% improvement in survival, stating that “VO 2max is a more powerful predictor of mortality among men than other established risk factors for cardiovascular disease (CVD).” Low CRF is also well established as an independent risk factor of T2D ( Booth et al. 2002 ) and CVD morbidity and mortality ( Kodama et al. 2009 ; Gupta et al. 2011 ). Similarly, Kokkinos et al. (2010) reported that men who transitioned from having low to high CRF decreased their mortality risk by ∼50% over an 8-yr period, whereas men who transitioned from having high to low CRF increased their mortality risk by ∼50%.

Importantly then, from the above paragraph, physical activity and inactivity are major environmental modulators of CRF, increasing and decreasing it, respectively, often through independent pathways. Findings from rats selectively bred for high or low intrinsic aerobic capacity show that rats bred for high capacity, which are also more physically active, have 28%–42% increases in life span compared to low-capacity rats ( Koch et al. 2011 ). Endurance exercise is well recognized to improve CRF and cardiometabolic risk factors. Exercise improves numerous factors speculated to limit VO 2max including, but not restricted to, the capacity to transport oxygen (e.g., cardiac output), oxygen diffusion to working muscles (e.g., capillary density, membrane permeability, muscle myoglobin content), and adenosine triphosphate (ATP) generation (e.g., mitochondrial density, protein concentrations).

Data from the HERITAGE Family Study has provided some of the first knowledge of genes associated with VO 2max plasticity because of endurance-exercise training. Following 6 wk of cycling training at 70% of pretraining VO 2max , Timmons et al. (2010) performed messenger RNA (mRNA) expression microarray profiling to identify molecules potentially predicting VO 2max training responses, and then assessed these molecular predictors to determine whether DNA variants in these genes correlated with VO 2max training responses. This approach identified 29 mRNAs in skeletal muscle and 11 single-nucleotide polymorphisms (SNPs) that predicted ∼50% and ∼23%, respectively, of the variability in VO 2max plasticity following aerobic training ( Timmons et al. 2010 ). Intriguingly, pretraining levels of these mRNAs were greater in subjects that achieved greater increases in VO 2max following aerobic training, and of the 29 mRNAs, >90% were unchanged with aerobic training, suggesting that alternative exercise intervention paradigms or pharmacological strategies may be needed to improve VO 2max in individuals with a low responder profile for the identified predictor genes ( Timmons et al. 2010 ). Keller et al. (2011) found that, in response to endurance training, improvements in VO 2max were associated with effectively up-regulating proangiogenic gene networks and miRNAs influencing the transcription factor–directed networks for runt-related transcription factor 1 (RUNX1), paired box gene 3 (PAC3), and sex-determining region Y box 9 (SOX9). Collectively, these results led the investigators to speculate that improvements in skeletal muscle oxygen sensing and angiogenesis are primary determinates in training responses in VO 2max ( Keller et al. 2011 ).

Clinically important concepts have emerged from the pioneering HERITAGE Family Study. One new clinical concept is that a threshold dose–response relationship influences the percentage of subjects responding with an increase in VO 2max to endurance training volumes (with volume being defined here as the product of intensity × duration), as previously published ( Slentz et al. 2005 , 2007 ). Ross et al. (2015) later extended the aforementioned Slentz et al. studies. After a 24-wk-long endurance training study ( Ross et al. 2015 ), percentages of women and men identified as nonresponders to the training (i.e., defined as not increasing their VO 2peak ) progressively fell inversely to a two stepwise progressive increase in endurance-exercise training volume, as described next. Thirty-nine percent (15 of 39) of training subjects did not increase their VO 2peak in response to the low-amount, low-intensity training; 18% (9 of 51) had no increase in VO 2peak in the group having high-amount, low-intensity training; and 0% (0 of 31) who underwent high-amount, high-intensity training did not increase their VO 2peak . A biological basis for the dose–response relationship in the previous sentence could be made from an analysis of interval training (IT) and IT/continuous-training studies published from 1965 to 2012 ( Bacon et al. 2013 ). A second older concept is being reinvigorated; Bacon et al. (2013) indicate that different endurance-exercise intensities and durations are needed for different systems in the body. They suggest that very short periods of high-intensity endurance-type exercise may be needed to reach a threshold for peripheral metabolic adaptations, but that longer training durations at lower intensities are required to see large changes in maximal cardiac output and VO 2max .

A comparable example exists for resistance training. Maximal resistance loads require a minimum of 2 min/per wk for each muscle group recruited by a specific maneuver to obtain a strength training adaptation [(8 contractions/set × 2 sec/contraction × 3 sets/day) × 2 days/wk) = 96 sec]. As of 2016, one opinion from Sarzynski et al. (2016) for the molecular mechanisms by which endurance exercise drives VO 2max include, but are not limited to, calcium signaling, energy sensing and partitioning, mitochondrial biogenesis, angiogenesis, immune functions, and regulation of autophagy and apoptosis.

Perhaps more importantly, lifelong aerobic exercise training preserves VO 2max into old age. CRF generally increases until early adulthood, then declines the remainder of life in sedentary humans ( Astrand 1956 ). The age-related decline in VO 2max is not trivial, as Schneider (2013) reported a ∼40% decline in healthy males and females spanning from 20 to 70 yr of age. However, cross-sectional data show that with lifelong aerobic exercise training, trained individuals often have the same VO 2max as a sedentary individual four decades younger ( Booth et al. 2012 ). Myers et al. (2002) found that low estimated VO 2max increases mortality 4.5-fold compared to high estimated VO 2max . They concluded, “Exercise capacity is a more powerful predictor of mortality among men than other established risk factors for cardiovascular disease.” Given the strong association between CRF, chronic disease, and mortality, we feel identifying the molecular transducers that cause age-related reductions in CRF may have profound implications for improving health span and delaying the onset of chronic disease. In two of our recent papers, transcriptomics was performed on the triceps muscle ( Toedebusch et al. 2016 ) and on the cardiac left ventricle ( Ruegsegger et al. 2017 ). We were addressing the question of what molecule initiates the beginning of the lifelong decline in aerobic capacity with aging. Aerobic capacity (VO 2max ) involves, at a minimum, the next systems/tissues, as oxygen travels through the mouth, airways, pulmonary membrane, pulmonary circulation, left heart, aorta/arteries/capillaries, and sarcoplasm/myoglobin to mitochondria. We allowed female rats access, or no access, to running wheels from 5 to 27 wk of age. Surprisingly, voluntary running had no effect on the delay in the beginning of the lifetime decrease in VO 2max . Our skeletal muscle transcriptomics elicited no molecular targets, whereas gene networks suggestive of influencing maximal stroke volume were identified in the left ventricle transcriptomics ( Ruegsegger et al. 2017 ).

Publications concerning the effects of exercise on the brain (from 54 to 216 papers listed on PubMed from 2007 to 2016) have increased 400%. In addition, a 2016 study ( Schuch et al. 2016 ) of three previous papers reported that humans with low- and moderate-CRF had 76% and 23%, respectively, increased risk of developing depression compared to high CRF in three publications. With this forming trend, the next section will consider exercise and brain health.

EXERCISE IMPROVES MENTAL HEALTH

Many studies support physical activity as a noninvasive therapy for mental health improvements in cognition ( Beier et al. 2014 ; Bielak et al. 2014 ; Tian et al. 2014 ), depression ( Kratz et al. 2014 ; McKercher et al. 2014 ; Mura et al. 2014 ), anxiety ( Greenwood et al. 2012 ; Nishijima et al. 2013 ; Schoenfeld et al. 2013 ), neurodegenerative diseases (i.e., Alzheimer’s and Parkinson’s disease) ( Bjerring and Arendt-Nielsen 1990 ; Mattson 2014 ), and drug addiction ( Zlebnik et al. 2012 ; Lynch et al. 2013 ; Peterson et al. 2014 ). In 1999, van Praag et al. (1999) showed the survival of newborn cells in the adult mouse dentate gyrus, a hippocampal region important for spatial recognition, is enhanced by voluntary wheel running. Similarly, spatial pattern separation and neurogenesis in the dentate gyrus are strongly correlated in 3-mo-old mice following 10 wk of voluntary wheel running ( Creer et al. 2010 ), and the development of new neurons in the dentate gyrus is coupled with the formation of new blood vessels ( Pereira et al. 2007 ). Many exercise-related improvements in cognitive function have been associated with local and systemic expression of growth factors in the hippocampus, notably, brain-derived neurotrophic factor (BDNF) ( Neeper et al. 1995 ; Cotman and Berchtold 2002 ). BDNF promotes many developmental functions in the brain, including neuronal cell survival, differentiation, migration, dendritic arborization, and synaptic plasticity ( Park and Poo 2013 ). In rat hippocampus, regular exercise promotes a progressive increase in BDNF protein for up to at least 3 mo ( Berchtold et al. 2005 ). In an opposite manner, BDNF mRNA in the hippocampus is rapidly decreased by the cessation of wheel running, suggesting BDNF expression is tightly related to exercise volume ( Widenfalk et al. 1999 ).

Findings by Wrann et al. (2013) highlight one mechanism by which endurance exercise may up-regulate BDNF expression. To summarize, Wrann et al. (2013) noted that exercise increases the activity of the estrogen-related receptor α (ERRα)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) complex, in turn increasing levels of the exercise-secreted factor FNDC5 in skeletal muscle and the hippocampus, whose cleavage products provide beneficial effects in the hippocampus by increasing BDNF gene expression. While future research should determine whether the FNDC5 cleavage-product was produced locally in hippocampal neurons or was secreted into the circulation, this finding eloquently displays one mechanism responsible for brain health benefits following exercise. Similarly, work by van Praag and colleagues suggests that exercise or pharmacological activation of AMP-activated protein kinase (AMPK) in skeletal muscle enhances indices of learning and memory, neurogenesis, and gene expression related to mitochondrial function in the hippocampus ( Kobilo et al. 2011 , 2014 ; Guerrieri and van Praag 2015 ).

Insulin-like growth factor 1 (IGF-1), is central to many exercise-induced adaptations in the brain. Like BDNF, physical activity increases circulatory IGF-1 levels and both exercise and infusion of IGF-1 increase BrdU + cell number and survivability in the hippocampus ( Trejo et al. 2001 ). Similarly, the protective effects of exercise on various brain lesions are nullified by anti-IGF-1 antibody ( Carro et al. 2001 ).

In 1979, Greist et al. (1979) provided evidence that running reduced depression symptoms similarly to psychotherapy. However, the precise mechanisms by which exercise prevents and/or treats depression remain largely unknown. Of the proposed mechanisms, increases in the availability of brain neurotransmitters and neurotrophic factors (e.g., BDNF, dopamine, glutamate, norepinephrine, serotonin) are perhaps the best studied. For example, tyrosine hydroxylase (TH) activity, the rate-limiting enzyme in dopamine formation, in the striatum, an area of the brain's reward system, is increased following 7 days of treadmill running in an intensity-dependent manner ( Hattori et al. 1994 ). Voluntary wheel running is also highly rewarding in rats, and voluntary wheel running in rats lowers the motivation to self-administer cocaine, suggesting exercise may be a viable strategy in the fight against drug addiction ( Larson and Carroll 2005 ).

Similar to the above examples, secreted factors from skeletal muscle have been linked to the regulation of depression. Agudelo et al. (2014) showed that exercise training in mice and humans, and overexpression of skeletal muscle PGC-1α1, leads to robust increases in kynurenine amino transferase (KAT) expression in skeletal muscle, an enzyme whose activity protects from stress-induced increases in depression in the brain by converting kynurenine into kynurenic acid. Additionally, overexpression of PGC-1α1 in skeletal muscle left mice resistant to stress, as evaluated by various behavioral assays indicative of depression ( Agudelo et al. 2014 ). Simultaneously, they report gene expression related to synaptic plasticity in the hippocampus, such as BDNF and CamkII, were unaffected by chronic mild stress compared to wild-type mice. Collectively, these findings suggest exercise-induced increases in skeletal muscle PGC-1α1 may be an important regulator of KAT expression in skeletal muscle, which, via modulation in plasma kynurenine levels, may alleviate stress-induced depression and promote hippocampal neuronal plasticity.

TYPE 2 DIABETES, MITOCHONDRIA, AND EXERCISE

T2d predictions show a pandemic.

In a 2001 Diabetes Care article ( Boyle et al. 2001 ), investigators at the U.S. Centers for Disease Control (CDC) predicted 29 million U.S. cases of T2D would be present in 2050. Unfortunately, the 2001 prediction of 29 million was reached in 2012! For 2012, the American Diabetes Association reported that 29 million Americans had diagnosed and undiagnosed T2D, which was 9% of the American population ( Dwyer-Lindgren et al. 2016 ). More rapid increases in T2D are now predicted by the CDC than in the previous estimate. The CDC now predicts a doubling or tripling in T2D in 2050. The tripling would mean that one out of three U.S. adults would have T2D in their lifetime by 2050 ( Boyle et al. 2010 ), which would be >100 million U.S. cases. The International Diabetes Federation (IDF) reports T2D cases worldwide. In 2015, the IDF reported that 344 and 416 million North American (including Caribbean) and worldwide adults, respectively, had T2D. Furthermore, the IDF predicts for 2040 that 413 and 642 million, respectively, will have T2D. In sum, T2D is now pandemic, and the pandemic will increase in numbers without current apparent action within the general public.

Type 2 Diabetes Prevalence Is Based on a Strong Genetic Predisposition

The Framingham study found that T2D risk in offspring was 3.5-fold and sixfold higher for a single and two diabetic parent(s), respectively, as compared to nondiabetic offspring ( Meigs et al. 2000 ). Thus, T2D is gene-based.

Noncoding regions of the human genome contain >90% of the >100 variants associated with both T2D and related traits that were observed in genome-wide association studies ( Scott et al. 2016 ). Another 2016 paper ( Kwak and Park 2016 ) lists at least 75 independent genetic loci that are associated with T2D. Taken together, T2D is a complex genetic disease ( Scott et al. 2016 ).

Type 2 Diabetes Is Modulated by Lifestyle, with Exercise as the More Powerful Lifestyle Factor

Three large-scale epidemiological studies have been performed on prediabetics, each in a different geographical location. The first study, and only study to have separate study arms for diet and exercise, was in China. The pure exercise intervention group had a 46% reduction in the onset of T2D, relative to the nontreated group, after 6 yr of the study ( Pan et al. 1997 ). Diet alone reduced T2D by 31% in the Chinese study. The second study on T2D was the Finnish Diabetes Prevention Study. It found a 58% reduction in T2D in the lifestyle intervention (combined diet and exercise) in its 522 prediabetic subjects after a mean study duration of 3.2 yr ( Tuomilehto et al. 2001 ). The latest of the three studies was in the U.S. Diabetes Prevention Program. The large randomized trial ( n = 3150 prediabetics) was stopped after 2.8 yr, because of harm to the control group. T2D prevalence in the high-risk adults was reduced by 58% with intensive lifestyle (diet and exercise) intervention, whereas the drug arm (metformin) of the study only reduced T2D by 31%, both compared to the noninnervation group ( Knowler et al. 2002 ). Thus, if differences in genetics in the above three differing ethnicities are not a factor, combined exercise and diet remain more effective in T2D prevention than the drug metformin two decades ago.

Exercise Increases Glucose by Signaling Independent of the Insulin Receptor

A single exercise bout increases glucose uptake by skeletal muscle, sidestepping the insulin receptor and thus insulin resistance in T2D patients ( Holloszy and Narahara 1965 ; Goodyear and Kahn 1998 ; Holloszy 2005 ). After insulin binding to its receptor, insulin initiates a downstream signaling cascade of tyrosine autophosphorylation of insulin receptor, insulin receptor substrate 1 (IRS-1) binding and phosphorylation, activation of a PI3K-dependent pathway, including key downstream regulators protein kinase B (Akt) and the Akt substrate of 160 kDa (AS160), ultimately promoting glucose transporter 4 (GLUT4) translocation to the plasma membrane ( Rockl et al. 2008 ; Stanford and Goodyear 2014 ). Despite normal GLUT4 levels, insulin fails to induce GLUT4 translocation in T2D ( Zierath et al. 2000 ). However, exercise activates a downstream insulin-signaling pathway at AS160 and TBC1 domain family member 1 (TBC1D1) ( Deshmukh et al. 2006 ; Maarbjerg et al. 2011 ), facilitating GLUT4 expression translocation to the plasma membrane independent of the insulin receptor. We contend that exercise could be considered as a very powerful tool to primarily attenuate the T2D pandemic.

Complex Biology of T2D Interactions with the Complex Biology of Exercise

An important consideration from the above is that T2D is such a genetically complex disease that a single gene has not been proven to be sufficiently causal to be effective, at this stage in time, to be a successful target for pharmacological treatment. The expectation for a single molecule target has been met for infectious diseases, which are often monogenic diseases. For example, a vaccine against smallpox was highly successful. Edward Jenner in 1796 produced the first successful vaccine. An important fact is that exercise is genetically complex. The literature allows us to speculate that exercise is at least as genetically complex as the approximately 75 genes associated with T2D ( Kwak and Park 2016 ). An example indicating that exercise is complex biology follows. RNA sequencing analysis of all 119 vastus lateralis muscle biopsies found that endurance training for 4 days/wk for 12 wk produced the differential expression of 3404 putative isoforms, belonging to 2624 different genes, many associated with oxidative ATP production in 23 women and men aged 29 yr old ( Lindholm et al. 2016 ). Our notion is that over 2600 genes suggests complex biology.

A “Case-Type” Study of the Molecular Underpinnings of Exercise, Mitochondria, and T2D Interactions

A PubMed search for the terms “diabetes mitochondria exercise molecular” elicited 74 papers. We arbitrarily selected some of the most recent 50 (spanning from mid-2014 into January 2017), with the assumption they would be representative of any other papers that we did not find in our search. Papers fell into our two arbitrary categories of single gene studies versus “omic”-type studies. First, subcategories of studies that develop themes will be arbitrarily presented.

Recent Studies Show Single Gene Manipulation Alters Mitochondrial Level and Running Performance

Numerous reports in the past couple of years observed that single gene manipulations increase mitochondrial gene expression and activity, which was also associated with increased exercise performance/capacity. A few of these are presented below:

  • Irisin was shown to increase oxidative metabolism in myocytes and increase PGC-1α mRNA and protein ( Vaughan et al. 2014 ), which extends the first observation made earlier in adipose tissue by Spiegelman ( Bostrom et al. 2012 ).
  • Patients with impaired glucose tolerance underwent low-intensity exercise training. Patients whose mitochondrial markers increased to levels that were measured in a separate cohort of nonexercised healthy individuals recovered normal glucose tolerance ( Osler et al. 2015 ). In opposition, those patients whose mitochondria markers did not improve, remained with impaired glucose tolerance.
  • In 2003, muscle PGC-1α mRNA was shown to be induced by endurance-exercise training in human skeletal muscle ( Short et al. 2003 ). PGC-1α was shown to have multiple isoforms ( Lin et al. 2002 ). After a 60-min cycling bout, human vastus lateralis biopsies were taken from both sexes in their mid-20s. Additional biopsies were taken 30 min, and at 2, 6, and 24 hr postexercise. At 30 min postexercise, PGC-1α-ex1b mRNA and PGC-1α mRNA increased 468- and 2.4-fold, respectively, whereas PGC-1α-ex1b protein and PGC-1α protein increased 3.1-fold and no change, respectively. Gidlund et al. (2015 ) interprets the above data as implying PGC-1α-ex1b could be responsible for other changes that have previously been recorded before the increase in total PGC-1α postexercise.
  • Mice with knockout of the kinin B1 receptor gene had higher mitochondrial DNA quantification and of mRNA levels of genes related to mitochondrial biogenesis in soleus and gastrocnemius muscles and had higher exercise times to exhaustion, but did not have higher VO 2max ( Reis et al. 2015 ).
  • Mice do not normally express cholesteryl ester transfer protein (CETP), which is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. Overexpression of CETP in mice after 6 wk on a high-fat diet increased treadmill running duration and distance, mitochondrial oxidation of glutamate/malate, but not palmitoylcarnitine oxidation, and doubled PGC-1α mRNA concentration ( Cappel et al. 2015 ).
  • The myokine musclin is a peptide secreted from exercising muscle during treadmill running. Removal of musclin release during running results in lowered VO 2max , lower skeletal muscle mitochondrial content and respiratory complex protein expression, and reduced exercise tolerance ( Subbotina et al. 2015 ).
  • Lactate dehydrogenase B (LDHB), which produces pyruvate from lactate, was overexpressed in mouse skeletal muscle. Increases in markers of skeletal muscle mitochondria were associated with increased running distance in a progressive speed test, and increased peak VO 2 ( Liang et al. 2016 ).
  • Another example of endurance-type exercise adaptations is the 2016 paper that transcription factor EB (TFEB) regulates metabolic flexibility in skeletal muscle independent of PGC-1α during endurance-type exercise ( Mansueto et al. 2017 ). Lack of metabolic flexibility, termed “metabolic inflexibility,” is important because it is common in T2D. One definition of metabolic inflexibility is its inability to rapidly switch between glucose and fatty acid substrates for ATP production when nutrient availability changes from high blood glucose levels immediately after a meal to decreasing below 100 mg/dl when not eating for hours after a meal. A clinical consequence of T2D-induced metabolic inflexibility is prolonged periods of hyperglycemia, because skeletal muscle is more insulin insensitive in T2D. In contrast, after sufficient endurance exercise, skeletal muscle increases its insulin sensitivity by a second pathway that is independent of proximal postreceptor insulin signaling (see Stephenson et al. 2014 for further discussion).

Studies Showing that Manipulation of One Signaling Molecule Does Not Alter Expression of All Genes with Mitochondrial Functions Found in Skeletal Muscles of Wild-Type Animals to Exercise Training

A 2010 review article ( Lira et al. 2010 ) concludes from gene-deletion studies that p38γ MAPK/PGC-1α signaling controls mitochondrial biogenesis’ adaptation to endurance exercise in skeletal muscle. Two studies do not completely agree with the conclusion in the review article. The Pilegaard laboratory published a 2008 study ( Leick et al. 2008 ) that did not confirm their hypothesis that PGC-1α was required for every metabolic protein adaptive increase after endurance-exercise training by skeletal muscle. They reported that PGC-1α was not required for endurance-training-induced increases in ALAS1, COXI, and cytochrome c expression ( Leick et al. 2008 ). Their interpretation, at that time, was that molecules other than PGC-1α can exert exercise-induced mitochondrial adaptations. A second study published in 2012 rendered a similar verdict. A 12-day program of endurance training led to the middle portion of the gastrocnemius muscle demonstrating a similar 60% increase in mitochondrial density in both wild-type and PGC-1α muscle-specific knockout mice (Myo-PGC-1αKO) ( Rowe et al. 2012 ). The paper concludes that PGC-1α is dispensable for endurance-exercise’s induction of skeletal muscle mitochondrial adaptations.

Exercise signaling targets have actions that are independent of PGC-1α, which is specific to endurance exercise. In 2002, two groups identified PGC-1β, a transcriptional coactivator closely related to PGC-1α ( Kressler et al. 2002 ; Lin et al. 2002 ). Later in 2012, the PGC-1α4 variant of PGC-1α was found to induce skeletal muscle hypertrophy and strength ( Ruas et al. 2012 ). The importance of the finding of a PGC-1α variant is that it partially explains the phenotypic variation for differing types of exercise. Since the 1970s ( Holloszy and Booth 1976 ), it has been appreciated that the biochemical and anatomical observations between endurance and resistance differed. For example, Holloszy and Booth (1976) noted in 1976 that, whereas endurance-type exercise markedly increased skeletal muscle mitochondrial density with very minor increases in muscle fiber diameter, strength-type exercise, in contrast, increased muscle fiber diameter without increases in skeletal muscle mitochondrial density. Taken together, a drug specific for PGC-1α will not likely mimic separate physical training for endurance, strength/resistance, and coordination types of exercise in the same subject. Thus, the common usage of the term exercise capacity is a misnomer because endurance training and resistance training were shown to have different exercise capacity phenotypes very long ago.

In a 2015 Diabetes paper ( Wong et al. 2015 ), Muoio’s laboratory concluded that changes in glucose tolerance and total body fat depended upon how much energy is expended in contracting muscle rather than muscle mitochondrial content or substrate selection. A finding to support the previous sentence was the glucose tolerance tests (GTTs). MCK-PGC-1α mice and their nontransgenic (NT) littermates were not different in GTT, with both being the most glucose intolerant after 10 wk of high-fat feeding. Adding 10 wk of voluntary wheel running to the two high-fat-feed groups during the next 10-wk period (weeks 11–20 of the experiment) lowered the glucose intolerance, and then during weeks 21–30 of the experiment, glucose intolerance was further lowered by adding 25% caloric restriction with the high-fat food and running during the final 10 wk. The percentage weight lost after 30 wk of high-fat feeding was positively related to greater running distances. No single front-runner gene candidate could be identified by principle component analysis. Taken together, the paper suggests “doubts” that pharmacological exercise mimetics that increase muscle oxidative capacity will be effective antiobesity and/or antidiabetic agents. Rather, Muoio and investigators suggest energy expenditure by muscle contraction induces localized shifts in energy balance inside the muscle fiber, which then initiates a broad network of metabolic intermediates regulating nutrient sensing and insulin action. A further discussion of complex biology produced by polygenicity continues next.

POLYGENICITY OF EXERCISE LEADS TO COMPLEX MULTISYSTEM RESPONSES TO IMPROVE HEALTH OUTCOMES

Multiples tissues, organs, and systems are influenced by physical activity, or the lack thereof ( Table 2 ).

Worsening of maximal functioning in selected major organ/tissue/systems that are caused by the lack of physical activity with growth, maturation, and aging

The higher their maximal function is before the end of each item’s maturation, the longer chances are that the quality of life will remain optimal. The breadth of the list implies that a single molecular target will not substitute for appropriate daily physical activity to prevent the loss of all listed items.

To present one extreme, that most will agree, one molecule will not describe the 1000s of molecules adapting to aerobic, resistance, and coordination exercise training. On the opposite extreme, many could likely agree that usage of the various “omics” underlying all adaptations to physical activity will differ (i.e., not be identical in most aspects) among the next list: various cell types within a tissue/organ, tissues/organs, and various intensities of physical activity (i.e., the thresholds among gene responses for health benefits will differ because of the presence of responders and nonresponders, or protein isoform type); during various types cycling (circadian or menstrual); postprandial versus fasting between meals; male and female; child, adult, and the elderly; trained and untrained; aerobic- and resistance-exercise types; and so forth. Others have repetitively written that only ∼59% of the risk reduction for all forms of CVD have been shown to be caused by effects through traditional factors ( Mora et al. 2007 ; Joyner and Green 2009 ). Thus, we pose the next question: what is the identity of all molecules in the yet-to-be-discovered gap between our knowledge of single gene functions and the totality of personalized prescription of physical activity to maximize the period of life free of any chronic disease, termed health span?

While approaches using single-gene manipulations are valuable tools, research must also focus on integrating exercise-responsive molecules into networks that maintain or improve health. This process will reveal complex, multisystem, polygenic networking essential for the advancement of many goals pertaining to exercise physiology, such as tailoring exercise prescriptions and implementing personalized medicine. One example is the developing myokine network with auto-, para-, and endocrine molecules. The first myokine interleukin (IL)-6 began to be described as early as 1994 by the Pedersen laboratory ( Ullum et al. 1994 ), with a history of its development as the first exercise myokine recounted in 2007 ( Pedersen et al. 2007 ). Since their discovery, myokine action within and at a distance from their origins in skeletal muscle have been increasingly studied, as schematically illustrated by Schnyder and Handschin (2015) ( Fig. 2 ).

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Figure provides an illustration of myokine production by skeletal muscle for actions within or at a distance. Myokine release promotes a high degree of intertissue cross talk. CNTF, Ciliary neurotrophic factor; OSM, oncostatin M; IL, interleukin; BDNF, brain-derived neurotrophic factor; VEGF, vascular endothelial growth factor. (From Schnyder and Handschin 2015 ; reprinted, with permission, courtesy of PMC Open Access.)

Similarly, maximal aerobic exercise is accompanied by tremendous stress on many systems, yet whole-body homeostasis is remarkably maintained. For example, world-class endurance athletes can increase whole-body energy production well over 20-fold ( Joyner and Coyle 2008 ), whereas maintaining blood glucose concentrations at resting levels ( Wasserman 2009 ). Intuitively, such effort would require sophisticated interorgan cross talk and polygenic integration of numerous functions.

Exercise Provides Too Many Benefits to “Fit into a Single Pill”

Despite the well-known benefits of exercise, most adults and many children lead relatively sedentary lifestyles and are not active enough to achieve the health benefits of exercise ( Warburton et al. 2006 ; Fried 2016 ). Accelerometry measurements suggest that >90% of U.S. individuals >12 yr of age and ∼50% of children aged 6–11 yr old fail to meet U.S. Federal physical activity guidelines ( Troiano et al. 2008 ). Given this incredibly low compliance, the identification of genetic and/or orally active agents that mimic the effects of endurance exercise might have high appeal for a majority of sedentary individuals. This high appeal has led to recent identification/development of exercise “mimetics.” In 2009, we set criteria for proper usage of the term “exercise mimetic,” based upon its common usage ( Booth and Laye 2009 ). We gave the Oxford English Dictionary’s definition of mimetic, “A synthetic compound that produces the same (or a very similar) effect as another (especially a naturally occurring) compound.” While many exercise “mimetics” activate signaling pathways commonly associated with muscle endurance, these agents have not completely mimicked all effects for all types of exercise. For example, the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), when given daily to rats over a 5-wk-period, did not increase maximal oxygen consumption (VO 2peak ) in the sedentary group of rats that were forced to run to VO 2peak on treadmills, as compared to sedentary rats receiving the vehicle ( Toedebusch et al. 2016 ). Thus, in our opinion, the published claim ( Narkar et al. 2008 ) that AICAR is an exercise mimetic is invalidated because it did not increase VO 2peak . While these agents may undoubtedly have specific health benefits, it is currently impractical to assume that all of the benefits of exercise can be replaced by “exercise mimetics.”

CONCLUDING REMARKS

Exercise is a powerful tool in the fight to prevent and treat numerous chronic diseases ( Table 1 ). Given its whole-body, health-promoting nature, the integrative responses to exercise should surely attract a great detail of interest as the notion of “exercise is medicine” continues to its integration into clinical settings.

ACKNOWLEDGMENTS

The authors disclose no conflicts of interest. Partial funding for this project was obtained from grants awarded to G.N.R. (AHA 16PRE2715005).

Editors: Juleen R. Zierath, Michael J. Joyner, and John A. Hawley

Additional Perspectives on The Biology of Exercise available at www.perspectivesinmedicine.org

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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 .

figure 1

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

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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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Supplementary Information

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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