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  • Review Article
  • Published:

Exerkines in health, resilience and disease

Nature Reviews Endocrinology volume 18, pages 273–289 (2022)Cite this article

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Abstract

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.

Key points

  • Although the benefits of exercise in enhancing health and treating disease are well-acknowledged, the molecular mechanisms underlying exercise-associated benefits remain ill-defined and are actively being investigated.

  • ‘Exerkines’ encompass a broad variety of signalling moieties released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways.

  • Exerkines can come in many forms, such as hormones, metabolites, proteins and nucleic acids; interest is increasing in moving beyond singular changes of specific factors to profiling exerkine alterations using ‘omics’ platforms.

  • There is burgeoning interest in the role of extracellular vesicles, which are membranous structures released from cells, in serving as important carriers of molecular signals and drivers of inter-organ crosstalk related to exercise.

  • Multiple organ systems, including the cardiometabolic system, nervous system and immune system, produce exerkines and are influenced by exerkines, which probably contributes to the pleiotropic and variable response to exercise.

  • Emerging research on exerkines suggests multiple promising avenues for translational research and therapeutic modulation to capture exercise-associated benefits; enhanced rigour in experimental design will facilitate comparison between studies.

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Fig. 1: The systemic effects of exercise.
Fig. 2: Examples of exerkines that affect the cardiometabolic system.
Fig. 3: Effects of exercise on the immune system.
Fig. 4: Effects of exercise on the nervous system.

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Acknowledgements

The authors thank A. Honkala (Stanford University) and N. C. Oldenburg (University of Minnesota) for their assistance with the manuscript. The workshop that set the foundation for this Review article was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). The listed authors acknowledge the support of the following grants. L.S.C.: NIH grant R01DK098203; B.H.G.: NIH grant U01AR071133; A.L.: Spanish Ministry of Economy and Competitiveness and Fondos FEDER (PI18/00139); C.M.: European Federation of the Study of Diabetes/MSD, Occitanie Region/FEDER funds (DIABKINES, MP0021755 and Enterosys); B.K.P.: TrygFonden for the Centre for PA Research (CFAS); A.P.: Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, NIH National Institute of Aging GEMSSTAR grant (1R03AG067960-01), and Applied Therapeutics; J.M.R.: NIH grant HL150327-01A1; H.v.P.: NIH National Institute on Aging (NIA)/NIH IRP and the FDOH Ed and Ethel Moore Alzheimer’s Disease Research program; K.I.S.: NIH grants R01-HL138738 and R01-AG060542; A.E.T.: National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; J.M.T.: NIH grant 1R01HL142879; S.T.: NIH grants U01AR071133; J.R.Z.: Swedish Research Council for Sport Science (P2018-0097), Swedish Research Council (Vetenskapsrådet) (2015-00165), and Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900); M.P.S.: NIH grants U24DK112348 and U54DK102556. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

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Authors and Affiliations

  1. Division of Diabetes Endocrinology and Metabolism, University of Minnesota, Minneapolis, MN, USA

    Lisa S. Chow

  2. Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Robert E. Gerszten & Jeremy M. Robbins

  3. Department of Pathology, McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA

    Joan M. Taylor

  4. Centre of Inflammation and Metabolism/Centre for PA Research (CIM/CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Bente K. Pedersen

  5. Stiles-Nicholson Brain institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, USA

    Henriette van Praag

  6. Human Performance Laboratory, Ball State University, Muncie, IN, USA

    Scott Trappe

  7. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

    Mark A. Febbraio

  8. Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Zorina S. Galis & Yunling Gao

  9. School of Kinesiology, University of Michigan, Ann Arbor, MI, USA

    Jacob M. Haus

  10. Division of Endocrinology, Nutrition, and Metabolism, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Ian R. Lanza

  11. Division of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School-the University of Queensland School of Medicine, New Orleans, LA, USA

    Carl J. Lavie

  12. Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Chih-Hao Lee

  13. Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain

    Alejandro Lucia

  14. Research Institute Hospital 12 de Octubre (‘imas12’), Madrid, Spain

    Alejandro Lucia

  15. CIBER en Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain

    Alejandro Lucia

  16. Institute of Metabolic and Cardiovascular Diseases, Team MetaDiab, Inserm UMR1297, Toulouse, France

    Cedric Moro

  17. Toulouse III University-Paul Sabatier (UPS), Toulouse, France

    Cedric Moro

  18. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Ambarish Pandey

  19. Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, USA

    Kristin I. Stanford

  20. National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK

    Alice E. Thackray

  21. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA

    Saul Villeda

  22. Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Victoria, Australia

    Matthew J. Watt

  23. Division of Diabetes, Endocrinology, & Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Ashley Xia

  24. Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden

    Juleen R. Zierath

  25. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Juleen R. Zierath

  26. Translational Research Institute, AdventHealth, Orlando, FL, USA

    Bret H. Goodpaster

  27. Department of Genetics, Stanford School of Medicine, Stanford, CA, USA

    Michael P. Snyder

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  1. Lisa S. Chow
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  2. Robert E. Gerszten
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Lisa S. Chow, Bret H. Goodpaster or Michael P. Snyder.

Ethics declarations

Competing interests

L.S.C. has received a Dexcom investigator initiated grant (product only). C.J.L. is a consultant for PAIhealth on their Personalized Activity Intelligence applications. A.P. is on the advisory board of Roche Diagnostics. M.P.S. is a cofounder and scientific advisory board member of Personalis, SensOmics, Qbio, January, Filtricine, Protos, NiMo, Mirvie, and an advisor for Genapsys. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks P. Atherton who co-reviewed the manuscript with D. Wilkinson, M. Fukui and E. Ziemann for their contribution to the peer review of this work.

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Related links

Molecular Transducers of Physical Activity Consortium: https://www.motrpac.org/

Resilience: https://ods.od.nih.gov/Research/resilience.aspx#defining

Supplementary information

Glossary

Resilience

Resilience is the ability of the body to resist, adapt to, recover or grow in response to stressors.

High-intensity interval training

High-intensity interval training is a form of exercise training characterized by bursts of high-intensity activity followed by less intense recovery periods.

Exerkines

Exerkines encompass a broad variety of signalling moieties that are released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways.

Acute exercise

Acute exercise is typically considered a single episode of exercise (often resistant or aerobic exercise) that is completed during one visit.

Chronic exercise

Chronic exercise is typically described as multiple exercise episodes (often resistant or aerobic exercise) performed over the course of weeks to months.

MicroRNA

MicroRNAs are non-protein-coding RNA molecules that are regulated in a transcriptional or post-transcriptional fashion to affect mRNA transcription and/or degradation.

Exosomes

Exosomes are a type of extracellular vesicle released by parent cells, which contain RNAs, proteins and lipids, to facilitate crosstalk between tissues.

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Chow, L.S., Gerszten, R.E., Taylor, J.M. et al. Exerkines in health, resilience and disease. Nat Rev Endocrinol 18, 273–289 (2022). https://doi.org/10.1038/s41574-022-00641-2

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