research paper of exercise physiology

Journal of Exercise Physiology

  • JEPonline Submission Guidelines
  • JEPonline Submission Payment
  • JEPonline Publishing Payment
  • JEMonline Submission Guidelines
  • JEMonline Submission Payment
  • JEMonline Publishing Payment
  • PEPonline Article Guidelines
  • PEPonline Submission
  • ASEPNewsletter Submissions
  • Journal of Professional Exercise Physiology
  • Exercise Physiology Books
  • Other Links

All articles and content are OPEN ACCESS (free, full text, from day of publication). ISSN 1097-9751

Published by the American Society of Exercise Physiologists , t he  Journal of Exercise Physiology online   is a professional peer reviewed Internet-based journal devoted to original research in exercise physiology. The journal is directed by the Editor-In-Chief with supporting editorial assistance via Associate Editors knowledgeable in the field of exercise physiology. JEP online is the first electronic peer reviewed exercise physiology journal in the history of the profession. It is founded for the purpose of disseminating exercise physiology research and to serve specifically the professional needs of the exercise physiologist. The Editors welcome both empirical and theoretical articles.

Copyright ©1997-2019 American Society of Exercise Physiologists. All Rights Reserved. Any reproduction or republication (in whole or in part) of any document or information found on this site for publication purposes or to otherwise take ownership is expressly prohibited, unless agreed to by the Editor-In-Chief of JEP online . ASEP does not charge readers or academic institutions for access to the journal articles.


Email: ( [email protected] )

Note: Unless stated otherwise by an email from Dr. Boone, send all manuscripts for possible publication in JEP online and JEM online via the ASEP steps indicated under each journal.

Current Issue


Past Issues









JEPonlineJUNE_2022 JEPonlineAPRIL_2022

February 2022

December 2021

October 2021 August 2021

February 2021

December 2020

October 2020

August 2020

February 2020

December 2019

November 2019 National Conference Abstracts

October 2019

August 2019

April 2019.docx

February 2019

December 2018

October 2018

August 2018

2018 February

2017 December

2017 October

2017 August

2017 February

2016 December

2016 October

2016 August

2016 February

2015 December

2015 Octobe r

2015 August

February 2015

December 2014

October 2014

August 2014

February 2014

December 2013

October 2013

August 2013

February 2013

December 2012

October 2012

August 2012

February 2012

December 2011

October 2011

August 2011

February 2011

December 2010

October 2010

August 2010

February 2010

December 2009

October 2009

August 2009

February 2009

December 2008

October 2008

August 2008

February 2008

December 2007

October 2007

August 2007

February 2006

December 2006

December 2005

October 2005

August 2005

February 2005

December 2004

October 2004

August 2004

February 2004

November 2003

August 2003

February 2003

November 2002

August 2002

February 2002

November 2001

August 2001

January 2001

October 2000

January 2000

October 1999

January 1999

October 1998

A century of exercise physiology: key concepts in …

  • Published: 17 December 2021
  • Volume 122 , pages 1–4, ( 2022 )
  • Michael I. Lindinger   ORCID: 1 &
  • Susan A. Ward 2  

6342 Accesses

6 Citations

16 Altmetric

Explore all metrics

Avoid common mistakes on your manuscript.

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.

Bainbridge F (1919) The physiology of muscular exercise, 1st edn. Longmans, Green and Company, London

Google Scholar  

Barcroft J (1934) Features in the architecture of physiological function. Cambridge University Press, Cambridge

Barr DP (1923) Studies in the physiology of muscular exercise. IV. Blood reaction and breathing. J Biol Chem 56:171–182.

Article   CAS   Google Scholar  

Barr DP, Himwich HE (1923a) Studies in the physiology of muscular exercise: II. Comparison of arterial and venous blood following vigorous exercise. J Biol Chem 55:525–537.

Barr DP, Himwich HE (1923b) Studies in the physiology of muscular exercise: III. Development and duration of changes in acid-base equilibrium. J Biol Chem 55:539–555.

Barr P, Himwich H, Green R (1923) Studies in the physiology of muscular exeercise. I. Changes in acid-base equilibrium following short periods of vigorous muscular exercise. J Physiol 55:495–523

CAS   Google Scholar  

Benedict F, Cathcart E (1913) Muscular work: a metabolic study with special reference to the efficiency of the human body as a machine, Carnegie I. Carnegie Institute, Washington

Book   Google Scholar  

Berryman JW (2010) Exercise is medicine: a historical perspective. Curr Sports Med Rep 9:195–201.

Article   PubMed   Google Scholar  

Bock A, Vancaulaert C, DB D et al (1928a) Studies in muscular activity. III. Dynamical changes occurring in man at work. J Physiol 66:136–160.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Bock AV, Dill DB, Talbott JH (1928b) Studies in muscular activity: I. Determination of the rate of circulation of blood in man at work. J Physiol 66:121–132.

Bock AV, Vancaulaert C, Dill DB et al (1928c) Studies in muscular activity: IV. The ‘steady state’ and the respiratory quotient during work. J Physiol 66:162–174.

Bock AV, Dill DB, Edwards HT (1932) Lactic acid in the blood of resting man. J Clin Invest 11:775–788.

Booth FW, Gordon SE, Carlson CJ, Hamilton MT (2000) Waging war on modern chronic diseases: primary prevention through exercise biology. J Appl Physiol 88:774–787.

Article   CAS   PubMed   Google Scholar  

Dill DB, Fölling A (1928) Studies in muscular activity: II. A nomographic description of expired air. J Physiol 66:133–135.

Dill DB, Talbott JH, Edwards HT (1930) Studies in muscular activity: VI. Response of several individuals to a fixed task. J Physiol 69:267–305.

Douglas CG (1927) Oliber-Sharpey Lectures on the coördination of the respiration and circulation with variations in bodily activity. Lancet 210:265–269.

Article   Google Scholar  

Douglas CG, Haldane JS (1909) The regulation of normal breathing. J Physiol 38:420–440.

Douglas CG, Haldane JS (1912) The capacity of the air passages under varying physiological conditions. J Physiol 45:235–238.

Fuller F (1705) 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. Robert Knaplock, London

Haldane JS, Priestley JG (1905) The regulation of the lung-ventilation. J Physiol 32:225–266.

Henderson Y (1923) Volume changes of the heart. Physiol Rev 3:165–208.

Hill AV, Lupton H (1923) Muscular exercise, lactic acid, and the supply and utilization of oxygen. QJM 16:135–171.

Hill AV, Meyerhof O (1923) Über die Vorgänge bei der Muskelkontraktion. Ergebnisse Der Physiol 22:299–327.

Himwich HE, Barr DP (1923) Studies in the physiology of muscular exercise: V. Oxygen relationships in the arterial blood. J Biol Chem 57:363–378.

Jervell O (1928) Investigation of the concentration of lactic acid in blood and urine, under physiologic and pathologic conditions. Acta Med Scand 68:5–135.

Krogh A (1919a) The supply of oxygen to the tissues and the regulation of the capillary circulation. J Physiol 52:457–474.

Krogh A (1919b) The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J Physiol 52:409–415.

Krogh A (1919c) The rate of diffusion of gases through animal tissues, with some remarks on the coefficient of invasion. J Physiol 52:391–408.

Krogh A, Lindhard J (1913a) The regulation of respiration and circulation during the initial stages of muscular work. J Physiol 47:112–136.

Krogh A, Lindhard J (1913b) The volume of the “dead space” in breathing. J Physiol 47:30–43.

Margaria R, Edwards HT, Dill DB (1933) The possible mechanisms of contracting and paying the oxygen debt and the rôle of lactic acid in muscular contraction. Am J Physiol 106:689–715.

Pilates J (1945) Return to life through contrology. J.J. Augustin, New York

Poole DC, Musch TI, Colburn TD. Oxygen flux from capillary to mitochondria: integration of contemporary discoveries. this issue

Shephard RJ (2013) The developing understanding of human health and fitness: The Post-Modern Era. Heal Fit J Canada 5:3–29

Talbott JH, Fölling A, Henderson LJ et al (1928) Studies in muscular activity. V. Changes and adaptations in running. J Biol Chem 78:445–463.

Tipton C (2014) Antiquity to the early years of the 20th Century. In: Tipton C (ed) History of Exercise Physiology. Human Kinetics, Champaign, pp 3–32

Chapter   Google Scholar  

Tipton C, Folk E (2014) Contributions from the Harvard Fatigue Laboratory. In: Tipton C (ed) History of Exercise Physiology. Human Kinetics, Champaign, pp 41–58

Download references

Author information

Authors and affiliations.

The Nutraceutical Alliance Inc., Burlington, ON, L7N 2Z9, Canada

Michael I. Lindinger

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

Susan A. Ward

You can also search for this author in PubMed   Google Scholar


Both MIL and SAW contributed equally to the writing and editing of the final document.

Corresponding author

Correspondence to Michael I. Lindinger .

Additional information

Communicated by Westerterp/Westerblad .

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Lindinger, M.I., Ward, S.A. A century of exercise physiology: key concepts in …. Eur J Appl Physiol 122 , 1–4 (2022).

Download citation

Received : 21 November 2021

Accepted : 10 December 2021

Published : 17 December 2021

Issue Date : January 2022


Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative


  • Find a journal
  • Publish with us
  • Track your research

U.S. flag

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

  • Publications
  • Account settings
  • Advanced Search
  • Journal List
  • Cold Spring Harb Perspect Med
  • 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 ).

An external file that holds a picture, illustration, etc.
Object name is cshperspectmed-BEX-029694_F1.jpg

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.


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.


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.


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.


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 ).

An external file that holds a picture, illustration, etc.
Object name is cshperspectmed-BEX-029694_F2.jpg

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.”


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.


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

  • Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, et al. 2014. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression . Cell 159 : 33–45. [ PubMed ] [ Google Scholar ]
  • Astrand PO. 1956. Human physical fitness with special reference to sex and age . Physiol Rev 36 : 307–335. [ PubMed ] [ Google Scholar ]
  • Bacon AP, Carter RE, Ogle EA, Joyner MJ. 2013. VO 2max trainability and high intensity interval training in humans: A meta-analysis . PLoS ONE 8 : e73182. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Beier M, Bombardier CH, Hartoonian N, Motl RW, Kraft GH. 2014. Improved physical fitness correlates with improved cognition in multiple sclerosis . Arch Phys Med Rehabil 95 : 1328–1334. [ PubMed ] [ Google Scholar ]
  • Berchtold NC, Chinn G, Chou M, Kesslak JP, Cotman CW. 2005. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus . Neuroscience 133 : 853–861. [ PubMed ] [ Google Scholar ]
  • Bielak AA, Cherbuin N, Bunce D, Anstey KJ. 2014. Preserved differentiation between physical activity and cognitive performance across young, middle, and older adulthood over 8 years . J Gerontol B Psychol Sci Soc Sci 69 : 523–532. [ PubMed ] [ Google Scholar ]
  • Bjerring P, Arendt-Nielsen L. 1990. Inhibition of histamine skin flare reaction following repeated topical applications of capsaicin . Allergy 45 : 121–125. [ PubMed ] [ Google Scholar ]
  • Blair SN, Kohl HW III, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. 1989. Physical fitness and all-cause mortality. A prospective study of healthy men and women . JAMA 262 : 2395–2401. [ PubMed ] [ Google Scholar ]
  • Booth FW, Laye MJ. 2009. Lack of adequate appreciation of physical exercise’s complexities can preempt appropriate design and interpretation in scientific discovery . J Physiol 587 : 5527–5539. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Booth FW, Chakravarthy MV, Gordon SE, Spangenburg EE. 2002. Waging war on physical inactivity: Using modern molecular ammunition against an ancient enemy . J Appl Physiol (1985) 93 : 3–30. [ PubMed ] [ Google Scholar ]
  • Booth FW, Roberts CK, Laye MJ. 2012. Lack of exercise is a major cause of chronic diseases . Compr Physiol 2 : 1143–1211. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, et al. 2012. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis . Nature 481 : 463–468. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Boyle JP, Honeycutt AA, Narayan KM, Hoerger TJ, Geiss LS, Chen H, Thompson TJ. 2001. Projection of diabetes burden through 2050: Impact of changing demography and disease prevalence in the U.S . Diabetes Care 24 : 1936–1940. [ PubMed ] [ Google Scholar ]
  • Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. 2010. Projection of the year 2050 burden of diabetes in the US adult population: Dynamic modeling of incidence, mortality, and prediabetes prevalence . Popul Health Metr 8 : 29. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Cappel DA, Lantier L, Palmisano BT, Wasserman DH, Stafford JM. 2015. CETP expression protects female mice from obesity-induced decline in exercise capacity . PLoS ONE 10 : e0136915. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Carro E, Trejo JL, Busiguina S, Torres-Aleman I. 2001. Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy . J Neurosci 21 : 5678–5684. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Cotman CW, Berchtold NC. 2002. Exercise: A behavioral intervention to enhance brain health and plasticity . Trends Neurosci 25 : 295–301. [ PubMed ] [ Google Scholar ]
  • Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ. 2010. Running enhances spatial pattern separation in mice . Proc Natl Acad Sci 107 : 2367–2372. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Deshmukh A, Coffey VG, Zhong Z, Chibalin AV, Hawley JA, Zierath JR. 2006. Exercise-induced phosphorylation of the novel Akt substrates AS160 and filamin A in human skeletal muscle . Diabetes 55 : 1776–1782. [ PubMed ] [ Google Scholar ]
  • Dwyer-Lindgren L, Mackenbach JP, van Lenthe FJ, Flaxman AD, Mokdad AH. 2016. Diagnosed and undiagnosed diabetes prevalence by county in the U.S., 1999–2012 . Diabetes Care 39 : 1556–1562. [ PubMed ] [ Google Scholar ]
  • Fried LP. 2016. Interventions for human frailty: Physical activity as a model . Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a025916. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
  • Gidlund EK, Ydfors M, Appel S, Rundqvist H, Sundberg CJ, Norrbom J. 2015. Rapidly elevated levels of PGC-1α-b protein in human skeletal muscle after exercise: Exploring regulatory factors in a randomized controlled trial . J Appl Physiol (1985) 119 : 374–384. [ PubMed ] [ Google Scholar ]
  • Goodyear LJ, Kahn BB. 1998. Exercise, glucose transport, and insulin sensitivity . Annu Rev Med 49 : 235–261. [ PubMed ] [ Google Scholar ]
  • Greenwood BN, Loughridge AB, Sadaoui N, Christianson JP, Fleshner M. 2012. The protective effects of voluntary exercise against the behavioral consequences of uncontrollable stress persist despite an increase in anxiety following forced cessation of exercise . Behav Brain Res 233 : 314–321. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Greist JH, Klein MH, Eischens RR, Faris J, Gurman AS, Morgan WP. 1979. Running as treatment for depression . Compr Psychiatry 20 : 41–54. [ PubMed ] [ Google Scholar ]
  • Guerrieri D, van Praag H. 2015. Exercise-mimetic AICAR transiently benefits brain function . Oncotarget 6 : 18293–18313. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Gupta S, Rohatgi A, Ayers CR, Willis BL, Haskell WL, Khera A, Drazner MH, de Lemos JA, Berry JD. 2011. Cardiorespiratory fitness and classification of risk of cardiovascular disease mortality . Circulation 123 : 1377–1383. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Hattori S, Naoi M, Nishino H. 1994. Striatal dopamine turnover during treadmill running in the rat: Relation to the speed of running . Brain Res Bull 35 : 41–49. [ PubMed ] [ Google Scholar ]
  • Holloszy JO. 2005. Exercise-induced increase in muscle insulin sensitivity . J Appl Physiol (1985) 99 : 338–343. [ PubMed ] [ Google Scholar ]
  • Holloszy JO, Booth FW. 1976. Biochemical adaptations to endurance exercise in muscle . Annu Rev Physiol 38 : 273–291. [ PubMed ] [ Google Scholar ]
  • Holloszy JO, Narahara HT. 1965. Studies of tissue permeability. X: Changes in permeability to 3-methylglucose associated with contraction of isolated frog muscle . J Biol Chem 240 : 3493–3500. [ PubMed ] [ Google Scholar ]
  • Joyner MJ, Coyle EF. 2008. Endurance exercise performance: The physiology of champions . J Physiol 586 : 35–44. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Joyner MJ, Green DJ. 2009. Exercise protects the cardiovascular system: Effects beyond traditional risk factors . J Physiol 587 : 5551–5558. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Keller P, Vollaard NB, Gustafsson T, Gallagher IJ, Sundberg CJ, Rankinen T, Britton SL, Bouchard C, Koch LG, Timmons JA. 2011. A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype . J Appl Physiol (1985) 110 : 46–59. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. 2002. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin . N Engl J Med 346 : 393–403. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Kobilo T, Yuan C, van Praag H. 2011. Endurance factors improve hippocampal neurogenesis and spatial memory in mice . Learn Mem 18 : 103–107. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Kobilo T, Guerrieri D, Zhang Y, Collica SC, Becker KG, van Praag H. 2014. AMPK agonist AICAR improves cognition and motor coordination in young and aged mice . Learn Mem 21 : 119–126. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Koch LG, Kemi OJ, Qi N, Leng SX, Bijma P, Gilligan LJ, Wilkinson JE, Wisloff H, Hoydal MA, Rolim N, et al. 2011. Intrinsic aerobic capacity sets a divide for aging and longevity . Circ Res 109 : 1162–1172. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y, et al. 2009. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: A meta-analysis . JAMA 301 : 2024–2035. [ PubMed ] [ Google Scholar ]
  • Kokkinos P, Myers J, Faselis C, Panagiotakos DB, Doumas M, Pittaras A, Manolis A, Kokkinos JP, Karasik P, Greenberg M, et al. 2010. Exercise capacity and mortality in older men: A 20-year follow-up study . Circulation 122 : 790–797. [ PubMed ] [ Google Scholar ]
  • Kratz AL, Ehde DM, Bombardier CH. 2014. Affective mediators of a physical activity intervention for depression in multiple sclerosis . Rehabil Psychol 59 : 57–67. [ PubMed ] [ Google Scholar ]
  • Kressler D, Schreiber SN, Knutti D, Kralli A. 2002. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor α . J Biol Chem 277 : 13918–13925. [ PubMed ] [ Google Scholar ]
  • Kwak SH, Park KS. 2016. Recent progress in genetic and epigenetic research on type 2 diabetes . Exp Mol Med 48 : e220. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Larson EB, Carroll ME. 2005. Wheel running as a predictor of cocaine self-administration and reinstatement in female rats . Pharmacol Biochem Behav 82 : 590–600. [ PubMed ] [ Google Scholar ]
  • Leick L, Wojtaszewski JF, Johansen ST, Kiilerich K, Comes G, Hellsten Y, Hidalgo J, Pilegaard H. 2008. PGC-1α is not mandatory for exercise- and training-induced adaptive gene responses in mouse skeletal muscle . Am J Physiol Endocrinol Metab 294 : E463–E474. [ PubMed ] [ Google Scholar ]
  • Liang X, Liu L, Fu T, Zhou Q, Zhou D, Xiao L, Liu J, Kong Y, Xie H, Yi F, et al. 2016. Exercise inducible lactate dehydrogenase B regulates mitochondrial function in skeletal muscle . J Biol Chem 291 : 25306–25318. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM. 2002. Peroxisome proliferator-activated receptor γ coactivator 1 β (PGC-1β ), a novel PGC-1-related transcription coactivator associated with host cell factor . J Biol Chem 277 : 1645–1648. [ PubMed ] [ Google Scholar ]
  • Lindholm ME, Giacomello S, Werne Solnestam B, Fischer H, Huss M, Kjellqvist S, Sundberg CJ. 2016. The impact of endurance training on human skeletal muscle memory, global isoform expression and novel transcripts . PLoS Genet 12 : e1006294. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Lira VA, Benton CR, Yan Z, Bonen A. 2010. PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity . Am J Physiol Endocrinol Metab 299 : E145–E161. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA. 2013. Exercise as a novel treatment for drug addiction: A neurobiological and stage-dependent hypothesis . Neurosci Biobehav Rev 37 : 1622–1644. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Maarbjerg SJ, Sylow L, Richter EA. 2011. Current understanding of increased insulin sensitivity after exercise—Emerging candidates . Acta Physiol (Oxf) 202 : 323–335. [ PubMed ] [ Google Scholar ]
  • Mansueto G, Armani A, Viscomi C, D’Orsi L, De Cegli R, Polishchuk EV, Lamperti C, Di Meo I, Romanello V, Marchet S, et al. 2017. Transcription factor EB controls metabolic flexibility during exercise . Cell Metab 25 : 182–196. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Mattson MP. 2014. Interventions that improve body and brain bioenergetics for Parkinson’s disease risk reduction and therapy . J Parkinsons Dis 4 : 1–13. [ PubMed ] [ Google Scholar ]
  • McKercher C, Sanderson K, Schmidt MD, Otahal P, Patton GC, Dwyer T, Venn AJ. 2014. Physical activity patterns and risk of depression in young adulthood: A 20-year cohort study since childhood . Soc Psychiatry Psychiatr Epidemiol 49 : 1823–1834. [ PubMed ] [ Google Scholar ]
  • Meigs JB, Cupples LA, Wilson PW. 2000. Parental transmission of type 2 diabetes: The Framingham Offspring Study . Diabetes 49 : 2201–2207. [ PubMed ] [ Google Scholar ]
  • Mokdad AH, Marks JS, Stroup DF, Gerberding JL. 2004. Actual causes of death in the United States, 2000 . JAMA 291 : 1238–1245. [ PubMed ] [ Google Scholar ]
  • Mora S, Cook N, Buring JE, Ridker PM, Lee IM. 2007. Physical activity and reduced risk of cardiovascular events: Potential mediating mechanisms . Circulation 116 : 2110–2118. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. 1953. Coronary heart-disease and physical activity of work . Lancet 265 : 1053–1057. [ PubMed ] [ Google Scholar ]
  • Mura G, Moro MF, Patten SB, Carta MG. 2014. Exercise as an add-on strategy for the treatment of major depressive disorder: A systematic review . CNS Spectr 19 : 496–508. [ PubMed ] [ Google Scholar ]
  • Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. 2002. Exercise capacity and mortality among men referred for exercise testing . N Engl J Med 346 : 793–801. [ PubMed ] [ Google Scholar ]
  • Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, et al. 2008. AMPK and PPARδ agonists are exercise mimetics . Cell 134 : 405–415. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Neeper SA, Gomez-Pinilla F, Choi J, Cotman C. 1995. Exercise and brain neurotrophins . Nature 373 : 109. [ PubMed ] [ Google Scholar ]
  • Nishijima T, Llorens-Martin M, Tejeda GS, Inoue K, Yamamura Y, Soya H, Trejo JL, Torres-Aleman I. 2013. Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice . Behav Brain Res 245 : 34–41. [ PubMed ] [ Google Scholar ]
  • Osler ME, Fritz T, Caidahl K, Krook A, Zierath JR, Wallberg-Henriksson H. 2015. Changes in gene expression in responders and nonresponders to a low-intensity walking intervention . Diabetes Care 38 : 1154–1160. [ PubMed ] [ Google Scholar ]
  • Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, et al. 1997. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study . Diabetes Care 20 : 537–544. [ PubMed ] [ Google Scholar ]
  • Park H, Poo MM. 2013. Neurotrophin regulation of neural circuit development and function . Nat Rev Neurosci 14 : 7–23. [ PubMed ] [ Google Scholar ]
  • Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. 2007. Role of myokines in exercise and metabolism . J Appl Physiol (1985) 103 : 1093–1098. [ PubMed ] [ Google Scholar ]
  • Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. 2007. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus . Proc Natl Acad Sci 104 : 5638–5643. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Peterson AB, Hivick DP, Lynch WJ. 2014. Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: Impact of sex and estrous cycle in rats . Psychopharmacology (Berl) 231 : 2661–2670. [ PubMed ] [ Google Scholar ]
  • Reis FC, Haro AS, Bacurau AV, Hirabara SM, Wasinski F, Ormanji MS, Moreira JB, Kiyomoto BH, Bertoncini CR, Brum PC, et al. 2015. Deletion of kinin B2 receptor alters muscle metabolism and exercise performance . PLoS ONE 10 : e0134844. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Rockl KS, Witczak CA, Goodyear LJ. 2008. Signaling mechanisms in skeletal muscle: Acute responses and chronic adaptations to exercise . IUBMB Life 60 : 145–153. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Ross R, de Lannoy L, Stotz PJ. 2015. Separate effects of intensity and amount of exercise on interindividual cardiorespiratory fitness response . Mayo Clin Proc 90 : 1506–1514. [ PubMed ] [ Google Scholar ]
  • Rowe GC, El-Khoury R, Patten IS, Rustin P, Arany Z. 2012. PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle . PLoS ONE 7 : e41817. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC, Greene NP, Wu J, Estall JL, Irving BA, et al. 2012. A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy . Cell 151 : 1319–1331. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Ruegsegger GN, Toedebusch RG, Braselton JF, Childs TE, Booth FW. 2017. Left ventricle transcriptomic analysis reveals connective tissue accumulation associates with initial age-dependent decline in VO 2peak from its lifetime apex . Physiol Genomics 49 : 53–66. [ PubMed ] [ Google Scholar ]
  • Sarzynski MA, Ghosh S, Bouchard C. 2016. Genomic and transcriptomic predictors of response levels to endurance exercise training . J Physiol 10.1113/JP272559. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
  • Schneider J. 2013. Age dependency of oxygen uptake and related parameters in exercise testing: An expert opinion on reference values suitable for adults . Lung 191 : 449–458. [ PubMed ] [ Google Scholar ]
  • Schnyder S, Handschin C. 2015. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise . Bone 80 : 115–125. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, Gould E. 2013. Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus . J Neurosci 33 : 7770–7777. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Schuch FB, Vancampfort D, Sui X, Rosenbaum S, Firth J, Richards J, Ward PB, Stubbs B. 2016. Are lower levels of cardiorespiratory fitness associated with incident depression? A systematic review of prospective cohort studies . Prev Med 93 : 159–165. [ PubMed ] [ Google Scholar ]
  • Scott LJ, Erdos MR, Huyghe JR, Welch RP, Beck AT, Wolford BN, Chines PS, Didion JP, Narisu N, Stringham HM, et al. 2016. The genetic regulatory signature of type 2 diabetes in human skeletal muscle . Nat Commun 7 : 11764. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Coenen-Schimke JM, Nair KS. 2003. Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity . Diabetes 52 : 1888–1896. [ PubMed ] [ Google Scholar ]
  • Slentz CA, Aiken LB, Houmard JA, Bales CW, Johnson JL, Tanner CJ, Duscha BD, Kraus WE. 2005. Inactivity, exercise, and visceral fat. STRRIDE: A randomized, controlled study of exercise intensity and amount . J Appl Physiol (1985) 99 : 1613–1618. [ PubMed ] [ Google Scholar ]
  • Slentz CA, Houmard JA, Kraus WE. 2007. Modest exercise prevents the progressive disease associated with physical inactivity . Exerc Sport Sci Rev 35 : 18–23. [ PubMed ] [ Google Scholar ]
  • Stanford KI, Goodyear LJ. 2014. Exercise and type 2 diabetes: Molecular mechanisms regulating glucose uptake in skeletal muscle . Adv Physiol Educ 38 : 308–314. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Stephenson EJ, Smiles W, Hawley JA. 2014. The relationship between exercise, nutrition and type 2 diabetes . Med Sport Sci 60 : 1–10. [ PubMed ] [ Google Scholar ]
  • Subbotina E, Sierra A, Zhu Z, Gao Z, Koganti SR, Reyes S, Stepniak E, Walsh SA, Acevedo MR, Perez-Terzic CM, et al. 2015. Musclin is an activity-stimulated myokine that enhances physical endurance . Proc Natl Acad Sci 112 : 16042–16047. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Tian Q, Erickson KI, Simonsick EM, Aizenstein HJ, Glynn NW, Boudreau RM, Newman AB, Kritchevsky SB, Yaffe K, Harris TB, et al. 2014. Physical activity predicts microstructural integrity in memory-related networks in very old adults . J Gerontol A Biol Sci Med Sci 69 : 1284–1290. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Timmons JA, Knudsen S, Rankinen T, Koch LG, Sarzynski M, Jensen T, Keller P, Scheele C, Vollaard NB, Nielsen S, et al. 2010. Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans . J Appl Physiol (1985) 108 : 1487–1496. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Toedebusch RG, Ruegsegger GN, Braselton JF, Heese AJ, Hofheins JC, Childs TE, Thyfault JP, Booth FW. 2016. AMPK agonist AICAR delays the initial decline in lifetime-apex VO 2peak , while voluntary wheel running fails to delay its initial decline in female rats . Physiol Genomics 48 : 101–115. [ PubMed ] [ Google Scholar ]
  • Trejo JL, Carro E, Torres-Aleman I. 2001. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus . J Neurosci 21 : 1628–1634. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Troiano RP, Berrigan D, Dodd KW, Masse LC, Tilert T, McDowell M. 2008. Physical activity in the United States measured by accelerometer . Med Sci Sports Exerc 40 : 181–188. [ PubMed ] [ Google Scholar ]
  • Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, et al. 2001. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance . N Engl J Med 344 : 1343–1350. [ PubMed ] [ Google Scholar ]
  • Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer-Kristensen J, Pedersen BK. 1994. Bicycle exercise enhances plasma IL-6 but does not change IL-1α, IL-1β, IL-6, or TNF-α pre-mRNA in BMNC . J Appl Physiol (1985) 77 : 93–97. [ PubMed ] [ Google Scholar ]
  • van Praag H, Kempermann G, Gage FH. 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus . Nat Neurosci 2 : 266–270. [ PubMed ] [ Google Scholar ]
  • Vaughan RA, Gannon NP, Barberena MA, Garcia-Smith R, Bisoffi M, Mermier CM, Conn CA, Trujillo KA. 2014. Characterization of the metabolic effects of irisin on skeletal muscle in vitro . Diabetes Obes Metab 16 : 711–718. [ PubMed ] [ Google Scholar ]
  • Warburton DE, Nicol CW, Bredin SS. 2006. Health benefits of physical activity: The evidence . CMAJ 174 : 801–809. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Wasserman DH. 2009. Four grams of glucose . Am J Physiol Endocrinol Metab 296 : E11–E21. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Widenfalk J, Olson L, Thoren P. 1999. Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain . Neurosci Res 34 : 125–132. [ PubMed ] [ Google Scholar ]
  • Wong KE, Mikus CR, Slentz DH, Seiler SE, DeBalsi KL, Ilkayeva OR, Crain KI, Kinter MT, Kien CL, Stevens RD, et al. 2015. Muscle-specific overexpression of PGC-1α does not augment metabolic improvements in response to exercise and caloric restriction . Diabetes 64 : 1532–1543. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. 2013. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway . Cell Metab 18 : 649–659. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • Zierath JR, Krook A, Wallberg-Henriksson H. 2000. Insulin action and insulin resistance in human skeletal muscle . Diabetologia 43 : 821–835. [ PubMed ] [ Google Scholar ]
  • Zlebnik NE, Anker JJ, Carroll ME. 2012. Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats . Psychopharmacology 224 : 387–400. [ PMC free article ] [ PubMed ] [ Google Scholar ]
  • 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: 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

23k Accesses

108 Citations

131 Altmetric

Metrics details

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.


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.


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 . (Accessed 8 June 2020).

Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, George SM, Olson RD. The physical activity guidelines for AmericansPhysical activity guidelines for AmericansPhysical activity guidelines for Americans. Jama. 2018;320(19):2020–8.

PubMed   Google Scholar  

Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, et al. Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the global burden of disease study 2013. BMJ. 2016;354:i3857.

PubMed   PubMed Central   Google Scholar  

Abell B, Glasziou P, Hoffmann T. The contribution of individual exercise training components to clinical outcomes in randomised controlled trials of cardiac rehabilitation: a systematic review and meta-regression. Sports Med Open. 2017;3(1):19.

Anderson D, Seib C, Rasmussen L. Can physical activity prevent physical and cognitive decline in postmenopausal women? A systematic review of the literature. Maturitas. 2014;79(1):14–33.

Barbaric M, Brooks E, Moore L, Cheifetz O. Effects of physical activity on cancer survival: a systematic review. Physiother Can. 2010;62(1):25–34.

Barlow PA, Otahal P, Schultz MG, Shing CM, Sharman JE. Low exercise blood pressure and risk of cardiovascular events and all-cause mortality: systematic review and meta-analysis. Atherosclerosis. 2014;237(1):13–22.

CAS   PubMed   Google Scholar  

Aljawarneh YM, Wardell DW, Wood GL, Rozmus CL. A systematic review of physical activity and exercise on physiological and biochemical outcomes in children and adolescents with type 1 diabetes. J Nurs Scholarsh. 2019.

Chastin SFM, De Craemer M, De Cocker K, Powell L, Van Cauwenberg J, Dall P, Hamer M, Stamatakis E. How does light-intensity physical activity associate with adult cardiometabolic health and mortality? Systematic review with meta-analysis of experimental and observational studies. Br J Sports Med. 2019;53(6):370–6.

Abdulla SY, Southerst D, Cote P, Shearer HM, Sutton D, Randhawa K, Varatharajan S, Wong JJ, Yu H, Marchand AA, et al. Is exercise effective for the management of subacromial impingement syndrome and other soft tissue injuries of the shoulder? A systematic review by the Ontario protocol for traffic injury management (OPTIMa) collaboration. Man Ther. 2015;20(5):646–56.

Alanazi MH, Parent EC, Dennett E. Effect of stabilization exercise on back pain, disability and quality of life in adults with scoliosis: a systematic review. Eur J Phys Rehabil Med. 2018;54(5):647–53.

Adsett JA, Mudge AM, Morris N, Kuys S, Paratz JD. Aquatic exercise training and stable heart failure: a systematic review and meta-analysis. Int J Cardiol. 2015;186:22–8.

Adamson BC, Ensari I, Motl RW. Effect of exercise on depressive symptoms in adults with neurologic disorders: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2015;96(7):1329–38.

Abdin S, Welch RK, Byron-Daniel J, Meyrick J. The effectiveness of physical activity interventions in improving well-being across office-based workplace settings: a systematic review. Public Health. 2018;160:70–6.

Albalawi H, Coulter E, Ghouri N, Paul L. The effectiveness of structured exercise in the south Asian population with type 2 diabetes: a systematic review. Phys Sportsmed. 2017;45(4):408–17.

Sellami M, Gasmi M, Denham J, Hayes LD, Stratton D, Padulo J, Bragazzi N. Effects of acute and chronic exercise on immunological parameters in the elderly aged: can physical activity counteract the effects of aging? Front Immunol. 2018;9:2187.

Hagen KB, Dagfinrud H, Moe RH, Østerås N, Kjeken I, Grotle M, Smedslund G. Exercise therapy for bone and muscle health: an overview of systematic reviews. BMC Med. 2012;10(1):167.

Burton DA, Stokes K, Hall GM. Physiological effects of exercise. Contin Educ Anaesth Crit Care Pain. 2004;4(6):185–8.

Google Scholar  

Kraemer WJ, Ratamess NA. Hormonal responses and adaptations to resistance exercise and training. Sports Med. 2005;35(4):339–61.

Nystoriak MA, Bhatnagar A. Cardiovascular effects and benefits of exercise. Front Cardiovasc Med. 2018;5:135.

CAS   PubMed   PubMed Central   Google Scholar  

Vina J, Sanchis-Gomar F, Martinez-Bello V, Gomez-Cabrera MC. Exercise acts as a drug; the pharmacological benefits of exercise. Br J Pharmacol. 2012;167(1):1–12.

Warburton DER, Bredin SSD. Health benefits of physical activity: a systematic review of current systematic reviews. Curr Opin Cardiol. 2017;32(5):541–56.

Excellence NIfHaC: Cardiovascular disease prevention public health guideline [PH25] Published date: June 2010. Available at: .

Excellence NIfHaC: Obesity prevention clinical guideline [CG43] published date: December 2006 Last updated: March 2015. Available at: .

Excellence NIfHaC: Physical activity for children and young people public health guideline [PH17] Published date: January 2009. Available at: .

Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 6 [updated September 2018] edition. Available from : The Cochrane Collaboration, 2011. 2011.

Bougioukas KI, Liakos A, Tsapas A, Ntzani E, Haidich A-B. Preferred reporting items for overviews of systematic reviews including harms checklist: a pilot tool to be used for balanced reporting of benefits and harms. J Clin Epidemiol. 2018;93:9–24.

Pollock M, Fernandes RM, Newton AS, Scott SD, Hartling L. The impact of different inclusion decisions on the comprehensiveness and complexity of overviews of reviews of healthcare interventions. Syst Rev. 2019;8(1):18.

Handoll H, Madhok R. Quality of Cochrane reviews. Another study found that most Cochrane reviews are of a good standard. BMJ. 2002;324(7336):545.

Petticrew M, Wilson P, Wright K, Song F. Quality of Cochrane reviews. Quality of Cochrane reviews is better than that of non-Cochrane reviews. BMJ. 2002;324(7336):545.

Shea B, Moher D, Graham I, Pham B, Tugwell P. A comparison of the quality of Cochrane reviews and systematic reviews published in paper-based journals. Eval Health Prof. 2002;25(1):116–29.

Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008.

Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, et al. Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action. BMC Med. 2018;16(1):18.

Bellou V, Belbasis L, Tzoulaki I, Evangelou E, Ioannidis JP. Environmental risk factors and Parkinson's disease: an umbrella review of meta-analyses. Parkinsonism Relat Disord. 2016;23:1–9.

Walter SD, Cook RJ. A comparison of several point estimators of the odds ratio in a single 2 x 2 contingency table. Biometrics. 1991;47(3):795–811.

Khan H, Sempos CT. Statistical methods in epidemiology. New York: Oxford University Press; 1989.

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

CAS   Google Scholar  

Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019): Cochrane; 2019. Available from .

Pieper D, Antoine SL, Mathes T, Neugebauer EA, Eikermann M. Systematic review finds overlapping reviews were not mentioned in every other overview. J Clin Epidemiol. 2014;67(4):368–75.

Adeniyi FB, Young T. Weight loss interventions for chronic asthma. Cochrane Database Syst Rev. 2012;7.

Al-Khudairy L, Loveman E, Colquitt JL, Mead E, Johnson RE, Fraser H, Olajide J, Murphy M, Velho RM, O'Malley C, et al. Diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. Cochrane Database Syst Rev. 2017;6.

Amorim Adegboye AR, Linne YM. Diet or exercise, or both, for weight reduction in women after childbirth. Cochrane Database Syst Rev. 2013;7.

Anderson L, Nguyen TT, Dall CH, Burgess L, Bridges C, Taylor RS. Exercise-based cardiac rehabilitation in heart transplant recipients. Cochrane Database Syst Rev. 2017;4.

Anderson L, Thompson DR, Oldridge N, Zwisler AD, Rees K, Martin N, Taylor RS. Exercise-based cardiac rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2016;1.

Andriolo RB, El Dib RP, Ramos L, Atallah Á, da Silva EMK. Aerobic exercise training programmes for improving physical and psychosocial health in adults with Down syndrome. Cochrane Database Syst Rev. 2010;5.

Araujo DN, Ribeiro CTD, Maciel ACC, Bruno SS, Fregonezi GAF, Dias FAL. Physical exercise for the treatment of non-ulcerated chronic venous insufficiency. Cochrane Database Syst Rev. 2016;12.

Ashworth NL, Chad KE, Harrison EL, Reeder BA, Marshall SC. Home versus center based physical activity programs in older adults. Cochrane Database Syst Rev. 2005;1.

Bartels EM, Juhl CB, Christensen R, Hagen KB, Danneskiold-Samsøe B, Dagfinrud H, Lund H. Aquatic exercise for the treatment of knee and hip osteoarthritis. Cochrane Database Syst Rev. 2016;3.

Beggs S, Foong YC, Le HCT, Noor D, Wood-Baker R, Walters JAE. Swimming training for asthma in children and adolescents aged 18 years and under. Cochrane Database Syst Rev. 2013;4.

Bergenthal N, Will A, Streckmann F, Wolkewitz KD, Monsef I, Engert A, Elter T, Skoetz N. Aerobic physical exercise for adult patients with haematological malignancies. Cochrane Database Syst Rev. 2014;11.

Bidonde J, Busch AJ, Schachter CL, Overend TJ, Kim SY, Góes SM, Boden C, Foulds HJA. Aerobic exercise training for adults with fibromyalgia. Cochrane Database Syst Rev. 2017;6.

Bidonde J, Busch AJ, van der Spuy I, Tupper S, Kim SY, Boden C. Whole body vibration exercise training for fibromyalgia. Cochrane Database Syst Rev. 2017;9.

Bidonde J, Busch AJ, Webber SC, Schachter CL, Danyliw A, Overend TJ, Richards RS, Rader T. Aquatic exercise training for fibromyalgia. Cochrane Database Syst Rev. 2014;10.

Braam KI, van der Torre P, Takken T, Veening MA, van Dulmen-den Broeder E, Kaspers GJL. Physical exercise training interventions for children and young adults during and after treatment for childhood cancer. Cochrane Database Syst Rev. 2016;3.

Bradt J, Shim M, Goodill SW. Dance/movement therapy for improving psychological and physical outcomes in cancer patients. Cochrane Database Syst Rev. 2015;1.

Broderick J, Crumlish N, Waugh A, Vancampfort D. Yoga versus non-standard care for schizophrenia. Cochrane Database Syst Rev. 2017;9.

Broderick J, Knowles A, Chadwick J, Vancampfort D. Yoga versus standard care for schizophrenia. Cochrane Database Syst Rev. 2015;10.

Broderick J, Vancampfort D. Yoga as part of a package of care versus standard care for schizophrenia. Cochrane Database Syst Rev. 2017;9.

Brown J, Ceysens G, Boulvain M. Exercise for pregnant women with gestational diabetes for improving maternal and fetal outcomes. Cochrane Database Syst Rev. 2017;6.

Busch AJ, Barber KA, Overend TJ, Peloso PMJ, Schachter CL. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev. 2007;4.

Busch AJ, Webber SC, Richards RS, Bidonde J, Schachter CL, Schafer LA, Danyliw A, Sawant A, Dal Bello-Haas V, Rader T, et al. Resistance exercise training for fibromyalgia. Cochrane Database Syst Rev. 2013;12.

Cameron ID, Dyer SM, Panagoda CE, Murray GR, Hill KD, Cumming RG, Kerse N. Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database Syst Rev. 2018;9.

Carson KV, Chandratilleke MG, Picot J, Brinn MP, Esterman AJ, Smith BJ. Physical training for asthma. Cochrane Database Syst Rev. 2013;9.

Carvalho APV, Vital FMR, Soares BGO. Exercise interventions for shoulder dysfunction in patients treated for head and neck cancer. Cochrane Database Syst Rev. 2012;4.

Cavalheri V, Granger C. Preoperative exercise training for patients with non-small cell lung cancer. Cochrane Database Syst Rev. 2017;6.

Cavalheri V, Tahirah F, Nonoyama ML, Jenkins S, Hill K. Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer. Cochrane Database Syst Rev. 2013;7.

Ceysens G, Rouiller D, Boulvain M. Exercise for diabetic pregnant women. Cochrane Database Syst Rev. 2006;3.

Choi BKL, Verbeek JH, Tam WWS, Jiang JY. Exercises for prevention of recurrences of low-back pain. Cochrane Database Syst Rev. 2010;1.

Colquitt JL, Loveman E, O'Malley C, Azevedo LB, Mead E, Al-Khudairy L, Ells LJ, Metzendorf MI, Rees K. Diet, physical activity, and behavioural interventions for the treatment of overweight or obesity in preschool children up to the age of 6 years. Cochrane Database Syst Rev. 2016;3.

Connolly B, Salisbury L, O'Neill B, Geneen LJ, Douiri A, Grocott MPW, Hart N, Walsh TS, Blackwood B. Exercise rehabilitation following intensive care unit discharge for recovery from critical illness. Cochrane Database Syst Rev. 2015;6.

Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE. Exercise for depression. Cochrane Database Syst Rev. 2013;9.

Corbetta D, Sirtori V, Castellini G, Moja L, Gatti R. Constraint-induced movement therapy for upper extremities in people with stroke. Cochrane Database Syst Rev. 2015;10.

Cramer H, Lauche R, Klose P, Lange S, Langhorst J, Dobos GJ. Yoga for improving health-related quality of life, mental health and cancer-related symptoms in women diagnosed with breast cancer. Cochrane Database Syst Rev. 2017;1.

Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev. 2012;11.

Dal Bello-Haas V, Florence JM. Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst Rev. 2013;5.

Dale MT, McKeough ZJ, Troosters T, Bye P, Alison JA. Exercise training to improve exercise capacity and quality of life in people with non-malignant dust-related respiratory diseases. Cochrane Database Syst Rev. 2015;11.

Daley A, Stokes-Lampard H, Thomas A, MacArthur C. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2014;11.

de Morton N, Keating JL, Jeffs K. Exercise for acutely hospitalised older medical patients. Cochrane Database Syst Rev. 2007;1.

Dobbins M, Husson H, DeCorby K, LaRocca RL. School-based physical activity programs for promoting physical activity and fitness in children and adolescents aged 6 to 18. Cochrane Database Syst Rev. 2013;2.

Doiron KA, Hoffmann TC, Beller EM. Early intervention (mobilization or active exercise) for critically ill adults in the intensive care unit. Cochrane Database Syst Rev. 2018;3.

Ekeland E, Heian F, Hagen KB, Abbott JM, Nordheim L. Exercise to improve self-esteem in children and young people. Cochrane Database Syst Rev. 2004;1.

Elbers RG, Verhoef J, van Wegen EEH, Berendse HW, Kwakkel G. Interventions for fatigue in Parkinson's disease. Cochrane Database Syst Rev. 2015;10.

Felbel S, Meerpohl JJ, Monsef I, Engert A, Skoetz N. Yoga in addition to standard care for patients with haematological malignancies. Cochrane Database Syst Rev. 2014;6.

Forbes D, Forbes SC, Blake CM, Thiessen EJ, Forbes S. Exercise programs for people with dementia. Cochrane Database Syst Rev. 2015;4.

Fransen M, McConnell S, Harmer AR, Van der Esch M, Simic M, Bennell KL. Exercise for osteoarthritis of the knee. Cochrane Database Syst Rev. 2015;1.

Fransen M, McConnell S, Hernandez-Molina G, Reichenbach S. Exercise for osteoarthritis of the hip. Cochrane Database Syst Rev. 2014;4.

Freitas DA, Holloway EA, Bruno SS, Chaves GSS, Fregonezi GAF, Mendonça K. Breathing exercises for adults with asthma. Cochrane Database Syst Rev. 2013;10.

Furmaniak AC, Menig M, Markes MH. Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database Syst Rev. 2016;9.

Giangregorio LM, MacIntyre NJ, Thabane L, Skidmore CJ, Papaioannou A. Exercise for improving outcomes after osteoporotic vertebral fracture. Cochrane Database Syst Rev. 2013;1.

Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson LM, Lamb SE. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2012;9.

Gorczynski P, Faulkner G. Exercise therapy for schizophrenia. Cochrane Database Syst Rev. 2010;5.

Grande AJ, Keogh J, Hoffmann TC, Beller EM, Del Mar CB. Exercise versus no exercise for the occurrence, severity and duration of acute respiratory infections. Cochrane Database Syst Rev. 2015;6.

Grande AJ, Reid H, Thomas EE, Nunan D, Foster C. Exercise prior to influenza vaccination for limiting influenza incidence and its related complications in adults. Cochrane Database Syst Rev. 2016;8.

Grande AJ, Silva V, Andriolo BNG, Riera R, Parra SA, Peccin MS. Water-based exercise for adults with asthma. Cochrane Database Syst Rev. 2014;7.

Gross A, Kay TM, Paquin JP, Blanchette S, Lalonde P, Christie T, Dupont G, Graham N, Burnie SJ, Gelley G, et al. Exercises for mechanical neck disorders. Cochrane Database Syst Rev. 2015;1.

Hageman D, Fokkenrood HJP, Gommans LNM, van den Houten MML, Teijink JAW. Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication. Cochrane Database Syst Rev. 2018;4.

Han A, Judd M, Welch V, Wu T, Tugwell P, Wells GA. Tai chi for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2004;3.

Han S, Middleton P, Crowther CA. Exercise for pregnant women for preventing gestational diabetes mellitus. Cochrane Database Syst Rev. 2012;7.

Hartley L, Dyakova M, Holmes J, Clarke A, Lee MS, Ernst E, Rees K. Yoga for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2014;5.

Hartley L, Flowers N, Lee MS, Ernst E, Rees K. Tai chi for primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2014;4.

Hartley L, Lee MS, Kwong JSW, Flowers N, Todkill D, Ernst E, Rees K. Qigong for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2015;6.

Hassett L, Moseley AM, Harmer AR. Fitness training for cardiorespiratory conditioning after traumatic brain injury. Cochrane Database Syst Rev. 2017;12.

Hayden J, van Tulder MW, Malmivaara A, Koes BW. Exercise therapy for treatment of non-specific low back pain. Cochrane Database Syst Rev. 2005;3.

Hay-Smith EJC, Herderschee R, Dumoulin C, Herbison GP. Comparisons of approaches to pelvic floor muscle training for urinary incontinence in women. Cochrane Database Syst Rev. 2011;12.

Heine M, van de Port I, Rietberg MB, van Wegen EEH, Kwakkel G. Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2015;9.

Heiwe S, Jacobson SH. Exercise training for adults with chronic kidney disease. Cochrane Database Syst Rev. 2011;10.

Hemmingsen B, Gimenez-Perez G, Mauricio D, Roqué i Figuls M, Metzendorf MI, Richter B. Diet, physical activity or both for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus. Cochrane Database Syst Rev. 2017;12.

Herbert RD, de Noronha M, Kamper SJ. Stretching to prevent or reduce muscle soreness after exercise. Cochrane Database Syst Rev. 2011;7.

Heymans MW, van Tulder MW, Esmail R, Bombardier C, Koes BW. Back schools for non-specific low-back pain. Cochrane Database Syst Rev. 2004;4.

Holland AE, Hill CJ, Jones AY, McDonald CF. Breathing exercises for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;10.

Howe TE, Rochester L, Neil F, Skelton DA, Ballinger C. Exercise for improving balance in older people. Cochrane Database Syst Rev. 2011;11.

Howe TE, Shea B, Dawson LJ, Downie F, Murray A, Ross C, Harbour RT, Caldwell LM, Creed G. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 2011;7.

Hurkmans E, van der Giesen FJ, Vliet Vlieland TPM, Schoones J, Van den Ende E. Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis. Cochrane Database Syst Rev. 2009;4.

Hurley M, Dickson K, Hallett R, Grant R, Hauari H, Walsh N, Stansfield C, Oliver S. Exercise interventions and patient beliefs for people with hip, knee or hip and knee osteoarthritis: a mixed methods review. Cochrane Database Syst Rev. 2018;4.

Jones M, Harvey A, Marston L, O'Connell NE. Breathing exercises for dysfunctional breathing/hyperventilation syndrome in adults. Cochrane Database Syst Rev. 2013;5.

Katsura M, Kuriyama A, Takeshima T, Fukuhara S, Furukawa TA. Preoperative inspiratory muscle training for postoperative pulmonary complications in adults undergoing cardiac and major abdominal surgery. Cochrane Database Syst Rev. 2015;10.

Kendrick D, Kumar A, Carpenter H, Zijlstra GAR, Skelton DA, Cook JR, Stevens Z, Belcher CM, Haworth D, Gawler SJ, et al. Exercise for reducing fear of falling in older people living in the community. Cochrane Database Syst Rev. 2014;11.

Kramer MS, McDonald SW. Aerobic exercise for women during pregnancy. Cochrane Database Syst Rev. 2006;3.

Lahart IM, Metsios GS, Nevill AM, Carmichael AR. Physical activity for women with breast cancer after adjuvant therapy. Cochrane Database Syst Rev. 2018;1.

Lane R, Harwood A, Watson L, Leng GC. Exercise for intermittent claudication. Cochrane Database Syst Rev. 2017;12.

Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2017;4.

Larun L, Nordheim LV, Ekeland E, Hagen KB, Heian F. Exercise in prevention and treatment of anxiety and depression among children and young people. Cochrane Database Syst Rev. 2006;3.

Lauret GJ, Fakhry F, Fokkenrood HJP, Hunink MGM, Teijink JAW, Spronk S. Modes of exercise training for intermittent claudication. Cochrane Database Syst Rev. 2014;7.

Lawrence M, Celestino Junior FT, Matozinho HHS, Govan L, Booth J, Beecher J. Yoga for stroke rehabilitation. Cochrane Database Syst Rev. 2017;12.

Lin CWC, Donkers NAJ, Refshauge KM, Beckenkamp PR, Khera K, Moseley AM. Rehabilitation for ankle fractures in adults. Cochrane Database Syst Rev. 2012;11.

Liu CJ, Latham NK. Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev. 2009;3.

Long L, Anderson L, Dewhirst AM, He J, Bridges C, Gandhi M, Taylor RS. Exercise-based cardiac rehabilitation for adults with stable angina. Cochrane Database Syst Rev. 2018;2.

Loughney LA, West MA, Kemp GJ, Grocott MPW, Jack S. Exercise interventions for people undergoing multimodal cancer treatment that includes surgery. Cochrane Database Syst Rev. 2018;12.

Macedo LG, Saragiotto BT, Yamato TP, Costa LOP, Menezes Costa LC, Ostelo R, Maher CG. Motor control exercise for acute non-specific low back pain. Cochrane Database Syst Rev. 2016;2.

Macêdo TMF, Freitas DA, Chaves GSS, Holloway EA, Mendonça K. Breathing exercises for children with asthma. Cochrane Database Syst Rev. 2016;4.

Martin A, Booth JN, Laird Y, Sproule J, Reilly JJ, Saunders DH. Physical activity, diet and other behavioural interventions for improving cognition and school achievement in children and adolescents with obesity or overweight. Cochrane Database Syst Rev. 2018;3.

McKeough ZJ, Velloso M, Lima VP, Alison JA. Upper limb exercise training for COPD. Cochrane Database Syst Rev. 2016;11.

McNamara RJ, McKeough ZJ, McKenzie DK, Alison JA. Water-based exercise training for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;12.

McNeely ML, Campbell K, Ospina M, Rowe BH, Dabbs K, Klassen TP, Mackey J, Courneya K. Exercise interventions for upper-limb dysfunction due to breast cancer treatment. Cochrane Database Syst Rev. 2010;6.

Mead E, Brown T, Rees K, Azevedo LB, Whittaker V, Jones D, Olajide J, Mainardi GM, Corpeleijn E, O'Malley C, et al. Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from the age of 6 to 11 years. Cochrane Database Syst Rev. 2017;6.

Meekums B, Karkou V, Nelson EA. Dance movement therapy for depression. Cochrane Database Syst Rev. 2015;2.

Meher S, Duley L. Exercise or other physical activity for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2006;2.

Mehrholz J, Kugler J, Pohl M. Water-based exercises for improving activities of daily living after stroke. Cochrane Database Syst Rev. 2011;1.

Mehrholz J, Kugler J, Pohl M. Locomotor training for walking after spinal cord injury. Cochrane Database Syst Rev. 2012;11.

Mehrholz J, Thomas S, Elsner B. Treadmill training and body weight support for walking after stroke. Cochrane Database Syst Rev. 2017;8.

Mishra SI, Scherer RW, Geigle PM, Berlanstein DR, Topaloglu O, Gotay CC, Snyder C. Exercise interventions on health-related quality of life for cancer survivors. Cochrane Database Syst Rev. 2012;8.

Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O. Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database Syst Rev. 2012;8.

Montgomery P, Dennis JA. Physical exercise for sleep problems in adults aged 60+. Cochrane Database Syst Rev. 2002;4.

Morris NR, Kermeen FD, Holland AE. Exercise-based rehabilitation programmes for pulmonary hypertension. Cochrane Database Syst Rev. 2017;1.

Muktabhant B, Lawrie TA, Lumbiganon P, Laopaiboon M. Diet or exercise, or both, for preventing excessive weight gain in pregnancy. Cochrane Database Syst Rev. 2015;6.

Ngai SPC, Jones AYM, Tam WWS. Tai chi for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2016;6.

Norton C, Cody JD. Biofeedback and/or sphincter exercises for the treatment of faecal incontinence in adults. Cochrane Database Syst Rev. 2012;7.

O'Brien K, Nixon S, Glazier R, Tynan AM. Progressive resistive exercise interventions for adults living with HIV/AIDS. Cochrane Database Syst Rev. 2004;4.

O'Brien K, Nixon S, Tynan AM, Glazier R. Aerobic exercise interventions for adults living with HIV/AIDS. Cochrane Database Syst Rev. 2010;8.

Østerås N, Kjeken I, Smedslund G, Moe RH, Slatkowsky-Christensen B, Uhlig T, Hagen KB. Exercise for hand osteoarthritis. Cochrane Database Syst Rev. 2017;1.

Page MJ, Green S, Kramer S, Johnston RV, McBain B, Chau M, Buchbinder R. Manual therapy and exercise for adhesive capsulitis (frozen shoulder). Cochrane Database Syst Rev. 2014;8.

Page MJ, Green S, McBain B, Surace SJ, Deitch J, Lyttle N, Mrocki MA, Buchbinder R. Manual therapy and exercise for rotator cuff disease. Cochrane Database Syst Rev. 2016;6.

Page MJ, O'Connor D, Pitt V, Massy-Westropp N. Exercise and mobilisation interventions for carpal tunnel syndrome. Cochrane Database Syst Rev. 2012;6.

Panebianco M, Sridharan K, Ramaratnam S. Yoga for epilepsy. Cochrane Database Syst Rev. 2017;10.

Perry A, Lee SH, Cotton S, Kennedy C. Therapeutic exercises for affecting post-treatment swallowing in people treated for advanced-stage head and neck cancers. Cochrane Database Syst Rev. 2016;8.

Radtke T, Nevitt SJ, Hebestreit H, Kriemler S. Physical exercise training for cystic fibrosis. Cochrane Database Syst Rev. 2017;11.

Regnaux JP, Lefevre-Colau MM, Trinquart L, Nguyen C, Boutron I, Brosseau L, Ravaud P. High-intensity versus low-intensity physical activity or exercise in people with hip or knee osteoarthritis. Cochrane Database Syst Rev. 2015;10.

Ren J, Xia J. Dance therapy for schizophrenia. Cochrane Database Syst Rev. 2013;10.

Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2005;1.

Risom SS, Zwisler AD, Johansen PP, Sibilitz KL, Lindschou J, Gluud C, Taylor RS, Svendsen JH, Berg SK. Exercise-based cardiac rehabilitation for adults with atrial fibrillation. Cochrane Database Syst Rev. 2017;2.

Romano M, Minozzi S, Bettany-Saltikov J, Zaina F, Chockalingam N, Kotwicki T, Maier-Hennes A, Negrini S. Exercises for adolescent idiopathic scoliosis. Cochrane Database Syst Rev. 2012;8.

Ryan JM, Cassidy EE, Noorduyn SG, O'Connell NE. Exercise interventions for cerebral palsy. Cochrane Database Syst Rev. 2017;6.

Saragiotto BT, Maher CG, Yamato TP, Costa LOP, Menezes Costa LC, Ostelo R, Macedo LG. Motor control exercise for chronic non-specific low-back pain. Cochrane Database Syst Rev. 2016;1.

Saunders DH, Sanderson M, Hayes S, Kilrane M, Greig CA, Brazzelli M, Mead GE. Physical fitness training for stroke patients. Cochrane Database Syst Rev. 2016;3.

Schulzke SM, Kaempfen S, Trachsel D, Patole SK. Physical activity programs for promoting bone mineralization and growth in preterm infants. Cochrane Database Syst Rev. 2014;4.

Seron P, Lanas F, Pardo Hernandez H, Bonfill Cosp X. Exercise for people with high cardiovascular risk. Cochrane Database Syst Rev. 2014;8.

Shaw KA, Gennat HC, O'Rourke P, Del Mar C. Exercise for overweight or obesity. Cochrane Database Syst Rev. 2006;4.

Shepherd E, Gomersall JC, Tieu J, Han S, Crowther CA, Middleton P. Combined diet and exercise interventions for preventing gestational diabetes mellitus. Cochrane Database Syst Rev. 2017;11.

Sibilitz KL, Berg SK, Tang LH, Risom SS, Gluud C, Lindschou J, Kober L, Hassager C, Taylor RS, Zwisler AD. Exercise-based cardiac rehabilitation for adults after heart valve surgery. Cochrane Database Syst Rev. 2016;3.

Silva IS, Fregonezi GAF, Dias FAL, Ribeiro CTD, Guerra RO, Ferreira GMH. Inspiratory muscle training for asthma. Cochrane Database Syst Rev. 2013;9.

States RA, Pappas E, Salem Y. Overground physical therapy gait training for chronic stroke patients with mobility deficits. Cochrane Database Syst Rev. 2009;3.

Strike K, Mulder K, Michael R. Exercise for haemophilia. Cochrane Database Syst Rev. 2016;12.

Takken T, Van Brussel M, Engelbert RH, van der Net JJ, Kuis W, Helders P. Exercise therapy in juvenile idiopathic arthritis. Cochrane Database Syst Rev. 2008;2.

Taylor RS, Sagar VA, Davies EJ, Briscoe S, Coats AJS, Dalal H, Lough F, Rees K, Singh SJ, Mordi IR. Exercise-based rehabilitation for heart failure. Cochrane Database Syst Rev. 2014;4.

Thomas D, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006;3.

Ussher MH, Taylor AH, Faulkner GEJ. Exercise interventions for smoking cessation. Cochrane Database Syst Rev. 2014;8.

Valentín-Gudiol M, Mattern-Baxter K, Girabent-Farrés M, Bagur-Calafat C, Hadders-Algra M, Angulo-Barroso RM. Treadmill interventions in children under six years of age at risk of neuromotor delay. Cochrane Database Syst Rev. 2017;7.

van der Heijden RA, Lankhorst NE, van Linschoten R, Bierma-Zeinstra SMA, van Middelkoop M. Exercise for treating patellofemoral pain syndrome. Cochrane Database Syst Rev. 2015;1.

Vloothuis JDM, Mulder M, Veerbeek JM, Konijnenbelt M, Visser-Meily JMA, Ket JCF, Kwakkel G, van Wegen EEH. Caregiver-mediated exercises for improving outcomes after stroke. Cochrane Database Syst Rev. 2016;12.

Voet NBM, van der Kooi EL. Riphagen, II, Lindeman E, van Engelen BGM, Geurts ACH: strength training and aerobic exercise training for muscle disease. Cochrane Database Syst Rev. 2013;7.

White CM, Pritchard J, Turner-Stokes L. Exercise for people with peripheral neuropathy. Cochrane Database Syst Rev. 2004;4.

Wieland LS, Skoetz N, Pilkington K, Vempati R, D'Adamo CR, Berman BM. Yoga treatment for chronic non-specific low back pain. Cochrane Database Syst Rev. 2017;1.

Williams AD, Bird ML, Hardcastle SGK, Kirschbaum M, Ogden KJ, Walters JAE. Exercise for reducing falls in people living with and beyond cancer. Cochrane Database Syst Rev. 2018;10.

Williams MA, Srikesavan C, Heine PJ, Bruce J, Brosseau L, Hoxey-Thomas N, Lamb SE. Exercise for rheumatoid arthritis of the hand. Cochrane Database Syst Rev. 2018;7.

Yamamoto S, Hotta K, Ota E, Matsunaga A, Mori R. Exercise-based cardiac rehabilitation for people with implantable ventricular assist devices. Cochrane Database Syst Rev. 2018;9.

Yamato TP, Maher CG, Saragiotto BT, Hancock MJ, Ostelo R, Cabral CMN, Menezes Costa LC, Costa LOP. Pilates for low back pain. Cochrane Database Syst Rev. 2015;7.

Yang ZY, Zhong HB, Mao C, Yuan JQ, Huang YF, Wu XY, Gao YM, Tang JL. Yoga for asthma. Cochrane Database Syst Rev. 2016;4.

Young J, Angevaren M, Rusted J, Tabet N. Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev. 2015;4.

Zainuldin R, Mackey MG, Alison JA. Optimal intensity and type of leg exercise training for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;11.

Mok A, Khaw K-T, Luben R, Wareham N, Brage S. Physical activity trajectories and mortality: population based cohort study. Bmj. 2019;365:l2323.

Ekelund U, Brown WJ, Steene-Johannessen J, Fagerland MW, Owen N, Powell KE, Bauman AE, Lee IM. Do the associations of sedentary behaviour with cardiovascular disease mortality and cancer mortality differ by physical activity level? A systematic review and harmonised meta-analysis of data from 850 060 participants. Br J Sports Med. 2019;53(14):886–94. . Epub 2018 Jul 10.

Article   PubMed   Google Scholar  

Ekelund U, Steene-Johannessen J, Brown WJ, Fagerland MW, Owen N, Powell KE, Bauman A, Lee IM. Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women. Lancet. 2016;388(10051):1302–10.

Lear SA, Hu W, Rangarajan S, Gasevic D, Leong D, Iqbal R, Casanova A, Swaminathan S, Anjana RM, Kumar R, et al. The effect of physical activity on mortality and cardiovascular disease in 130000 people from 17 high-income, middle-income, and low-income countries: the PURE study. Lancet. 2017;390(10113):2643–54.

Sattelmair J, Pertman J, Ding EL, Kohl HW 3rd, Haskell W, Lee IM. Dose response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation. 2011;124(7):789–95.

Heyman E, Gamelin FX, Goekint M, Piscitelli F, Roelands B, Leclair E, Di Marzo V, Meeusen R. Intense exercise increases circulating endocannabinoid and BDNF levels in humans--possible implications for reward and depression. Psychoneuroendocrinology. 2012;37(6):844–51.

Horton R. Offline: the gravy train of systematic reviews. Lancet. 2019;394(10211):1790.

Guthold R, Stevens GA, Riley LM, Bull FC. Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants. Lancet Glob Health. 2018;6(10):e1077–86.

Fletcher GF, Landolfo C, Niebauer J, Ozemek C, Arena R, Lavie CJ. Promoting physical activity and exercise: JACC health promotion series. J Am Coll Cardiol. 2018;72(14):1622–39.

Download references


Not applicable.

There was no funding source for this study. Open Access funding enabled and organized by Projekt DEAL.

Author information

Authors and affiliations.

Kleijnen Systematic Reviews Ltd., York, UK

Pawel Posadzki

Nanyang Technological University, Singapore, Singapore

Institute for Research in Operative Medicine, Witten/Herdecke University, Witten, Germany

Dawid Pieper, Nadja Könsgen & Annika Lena Neuhaus

School of Medicine, Keele University, Staffordshire, UK

Jozef Pilsudski University of Physical Education in Warsaw, Faculty Physical Education and Health, Biala Podlaska, Poland

Hubert Makaruk

Health Outcomes Division, University of Texas at Austin College of Pharmacy, Austin, USA

Monika Semwal

You can also search for this author in PubMed   Google Scholar


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.

Corresponding author

Correspondence to Dawid Pieper .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

The authors declare that they have no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit . The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

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).

Download citation

Received : 01 April 2020

Accepted : 08 November 2020

Published : 16 November 2020


Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

  • Effectiveness

BMC Public Health

ISSN: 1471-2458

research paper of exercise physiology


  1. (PDF) Physiological responses to exercise

    research paper of exercise physiology

  2. Exercise Physiology: A Brief History and Recommendations

    research paper of exercise physiology

  3. Exercise Physiology lab report

    research paper of exercise physiology

  4. 9781259913884: Exercise Physiology Laboratory Manual

    research paper of exercise physiology

  5. (PDF) Editorial: Children's Exercise Physiology

    research paper of exercise physiology

  6. Exercise Physiology: The Physiology of Exercise Testing, Volume 1

    research paper of exercise physiology


  1. Physiology Practical (2) part-1

  2. Exercise Physiology Interview Research Topic Extra Credit Video

  3. Physiology Paper 1st 2023 mbbs

  4. Gnm 1st year Paper Anatomy/Physiology/Microbiology || Gnm Previous Question Paper 2023

  5. Human Physiology (General) 4th Semester Paper

  6. Human Physiology (General) 2nd Semester Paper


  1. Download .nbib

    Figure 1 illustrates the increase in publications in exercise physiology since 1980, as well as its representation in highly regarded scientific and clinical journals such as the Proceedings of the National Academy of Sciences and the Journal of the American Medical Association, respectively.

  2. Exercise and health: historical perspectives and new insights

    The application of molecular biology techniques and “omics” approaches to questions in exercise biology has opened new lines of investigation to better understand the beneficial effects of exercise and, in so doing, inform the optimization of exercise regimens and the identification of novel therapeutic strategies to enhance health and well-being.

  3. Journal of Exercise Physiology - American Society of Exercise ...

    Published by the American Society of Exercise Physiologists, t he Journal of Exercise Physiologyonline is a professional peer reviewed Internet-based journal devoted to original research in exercise physiology.

  4. A century of exercise physiology: key concepts in - Springer

    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 Archi...

  5. Frontiers in Physiology | Exercise Physiology

    A forum for research across all aspects of exercise physiology, from the production of the motor command, to the execution of the exercise task and any supporting activity.

  6. Editorial: Insights in exercise physiology: 2021 - PMC

    Part of the current scope of research in exercise physiology is represented by 11 papers contributing to the Research Topic “Insights in Exercise Physiology: 2021,” from different areas. Go to: Cardiovascular exercise physiology

  7. Health Benefits of Exercise - PMC - National Center for ...

    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 ).

  8. Training for strength and hypertrophy: an evidence-based ...

    Otherwise, this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest statement. Nothing declared. References and recommended reading. Papers of particular interest, published within the period of review, have been highlighted as: • of special interest

  9. Exercise/physical activity and health outcomes: an overview ...

    Background 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 ...