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The potential of endurance exercise-derived exosomes to treat metabolic diseases

Key Points

  • Epidemiological data demonstrate that endurance exercise confers multisystemic benefits on human health, and mitigates the effects of metabolic diseases including obesity and type 2 diabetes mellitus (T2DM)

  • A variety of peptides and microRNA (miRNA) species (exerkines) are altered in response to acute and chronic endurance exercise that can influence the pathophysiology of obesity and T2DM through endocrine-like effects

  • Exosomes are endocrine-like intercellular communication vesicles that carry proteins, miRNA and other nucleic acids between cells and tissues, and promote cross talk between organs

  • The specific physiological roles of exosomes and microvesicles have yet to be fully elucidated owing to controversies in current isolation methodologies

  • Isolation techniques and comprehensive particle characterization are essential factors to consider in the study of exosomes and microvesicles

  • We hypothesize that many of the exerkines that mitigate obesity and T2DM, and positively regulate metabolic health are contained within exosomes; future therapies for obesity and T2DM might involve modified exosomes enriched with exerkines

Abstract

Endurance exercise-mediated multisystemic adaptations are known to mitigate metabolism-related disorders such as obesity and type 2 diabetes mellitus (T2DM). However, the underlying molecular mechanisms that promote crosstalk between organs and orchestrate the pro-metabolic effects of endurance exercise remain unclear. Exercise-induced release of peptides and nucleic acids from skeletal muscle and other organs (collectively termed 'exerkines') has been implicated in mediating these systemic adaptations. Given that the extracellular milieu is probably not a hospitable environment for labile exerkines, a lipid vehicle-based mode of delivery has originated over the course of evolution. Two types of extracellular vesicles, exosomes and microvesicles, have been shown to contain proteins and nucleic acids that participate in a variety of physiological and pathological processes. Exosomes, in particular, have been shown to facilitate the exchange of peptides, microRNA, mRNA and mitochondrial DNA between cells and tissues. Intriguingly, circulatory extracellular vesicle content increases in an intensity-dependant manner in response to endurance exercise. We propose that the systemic benefits of exercise are modulated by exosomes and/or microvesicles functioning in an autocrine, paracrine and/or endocrine manner. Furthermore, we posit that native or modified exosomes, and/or microvesicles enriched with exerkines will have therapeutic utility in the treatment of obesity and T2DM.

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Figure 1: Biogenesis and secretion of exosomes and microvesicles.
Figure 2: Exosomes mediate the systemic benefits of endurance exercise.
Figure 3: Acute endurance exercise promotes dynamic secretion of exosomes from skeletal muscle.

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Acknowledgements

M.A.T. receives grant support for work on exosomes and exercise from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC). A. Safdar is supported by a CIHR Banting Postdoctoral Fellowship during part of his tenure doing exercise and exosome research. A. Saleem is supported by an NSERC Postdoctoral Fellowship. The authors wish to thank Anusheh Saleem for her assistance with the original artwork submitted with this review.

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A. Safdar, A. Saleem and M.A.T. reviewed the literature, made substantial contributions to discussions of the content, wrote the article, and edited the manuscript prior to submission.

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Correspondence to Mark A. Tarnopolsky.

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Competing interests

M.A.T. has an equity stake in Exerkine Corporation. M.A.T. is the Chief Executive Officer and President, and A. Safdar is the Chief Scientific Officer of Exerkine Corporation. Exerkine has filed patents for the use of exerkines and exersomes to treat metabolic disease, and the use of exosomes to treat genetic disorders.

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FURTHER INFORMATION

Vesiclepedia

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ExoCarta

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Glossary

Endurance exercise

Long-duration exercise at submaximal intensities of 40–80% of maximal oxygen consumption.

Myokine

Any peptide, microRNA, mRNA or other circulating RNA species that is released by skeletal muscle into the circulation in response to exercise.

Exerkine

Any peptide, microRNA, mRNA or other circulating RNA species that is released into the circulation in response to exercise.

Extracellular vesicle

Any membrane-bound vesicle released into the extracellular fluid, including apoptotic bodies, microvesicles and exosomes.

Exosomes

The smallest (20–140 nm) form of extracellular vesicle derived from inward budding of the late endosome that are either released to the extracellular environment or to the lysosome.

Microvesicles

Intermediate sized (100–1,000 nm) extracellular vesicles formed from the plasma membrane and released into the extracellular environment.

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Safdar, A., Saleem, A. & Tarnopolsky, M. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol 12, 504–517 (2016). https://doi.org/10.1038/nrendo.2016.76

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