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  • Review Article
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Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit

Nature Reviews Endocrinology volume 16, pages 495–505 (2020)Cite this article

Subjects

Abstract

Exercise is fundamental for good health, whereas physical inactivity underpins many chronic diseases of modern society. It is well appreciated that regular exercise improves metabolism and the metabolic phenotype in a number of tissues. The phenotypic alterations observed in skeletal muscle are partly mediated by transcriptional responses that occur following each individual bout of exercise. This adaptive response increases oxidative capacity and influences the function of myokines and extracellular vesicles that signal to other tissues. Our understanding of the epigenetic and transcriptional mechanisms that mediate the skeletal muscle gene expression response to exercise as well as of their upstream signalling pathways has advanced substantially in the past 10 years. With this knowledge also comes the opportunity to design new therapeutic strategies based on the biology of exercise for a variety of chronic conditions where regular exercise might be a challenge. This Review provides an overview of the beneficial adaptive responses to exercise and details the molecular mechanisms involved. The possibility of designing therapeutic interventions based on these molecular mechanisms is addressed, using relevant examples that have exploited this approach.

Key points

  • Exercise is effective in the primary prevention of 35 chronic diseases.

  • The adaptive response to exercise, which is mediated in part by transcriptional alterations in metabolic and other genes, is an important contributor to these health benefits.

  • Identifying the mechanisms that mediate the exercise adaptive response could uncover molecular targets to guide the design of new medicines to better treat chronic diseases.

  • A number of signalling, epigenetic and transcriptional molecules identified as contributing to the exercise adaptive response have been targeted pharmacologically to deliver health benefits in proof-of-concept studies.

  • A further understanding of the complexities of the molecular responses to exercise will provide new opportunities to engage these mechanisms therapeutically.

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Fig. 1: Exercise adaptations and their theoretical therapeutic potential.
Fig. 2: The MEF2–class IIa HDAC axis as a target to replicate aspects of the exercise adaptive response.

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Acknowledgements

The authors acknowledge the many researchers whose work they have not been able to cite in this Review. Original work by the authors was supported by the Diabetes Australia Research Program and the National Health and Medical Research Council of Australia.

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  1. Metabolic Research Unit, School of Medicine and Institute for Mental and Physical Health and Clinical Translation (iMPACT), Deakin University, Geelong, Victoria, Australia

    Sean L. McGee

  2. Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia

    Mark Hargreaves

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The authors contributed equally to all aspects of the article.

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Correspondence to Sean L. McGee or Mark Hargreaves.

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Competing interests

Both authors hold equity in Imitex Pty Ltd., a drug discovery start-up that was spun out from papers published by the authors that have identified the MEF2-class IIa HDAC axis as a druggable target to replicate aspects of the exercise adaptive response. This pathway is discussed in the current manuscript, along with many others that have been studied within the field.

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Nature Reviews Endocrinology thanks M.H. Laughlin and M. Tarnopolsky for their contribution to the peer review of this work.

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Glossary

Type II fibres

Muscle fibres that are fast twitch, are able to produce large amounts of tension, have a fairly high reliance on anaerobic ATP production and fatigue easily.

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McGee, S.L., Hargreaves, M. Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit. Nat Rev Endocrinol 16, 495–505 (2020). https://doi.org/10.1038/s41574-020-0377-1

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