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  • Review Article
  • Published:

The ever-expanding myokinome: discovery challenges and therapeutic implications

Nature Reviews Drug Discovery volume 15, pages 719–729 (2016)Cite this article

Subjects

Key Points

  • Myokines are proteins or peptides that are upregulated and secreted from skeletal muscle to carry out paracrine or endocrine functions.

  • The concept that stimulated muscle secretes factors that partially mediate the benefits of exercise on health is attractive, as it raises the possibility that these peptides might be manipulated for therapeutic gain.

  • There are many technical hurdles to the discovery of new myokines, but developing methodologies such as proteomics, genetic modification of mice by CRISPR and parabiosis are well suited for myokine discovery and validation.

  • With the increasing realization that brown fat and the 'browning' of adipose tissue represents a therapeutic avenue for treating obesity and metabolic disease, putative myokines irisin and meteorin-like may have a role in this research setting. The myokines interleukin-6 (IL-6) and SPARC (secreted protein acidic and rich in cysteine) have been implicated in the prevention of cancers by exercise.

  • It is anticipated that future research will uncover more novel myokines with the potential to treat diseases that are known to be prevented by regular exercise.

Abstract

Exercise reduces the risk of a multitude of disorders, from metabolic disease to cancer, but the molecular mechanisms mediating the protective effects of exercise are not completely understood. The realization that skeletal muscle is an endocrine organ capable of secreting proteins termed 'myokines', which participate in tissue crosstalk, provided a critical link in the exercise–health paradigm. However, the myokine field is still emerging, and several challenges remain in the discovery and validation of myokines. This Review considers these challenges and highlights some recently identified novel myokines with the potential to be therapeutically exploited in the treatment of metabolic disease and cancer.

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Figure 1: The opposing effects of physical inactivity and exercise on disease risk.
Figure 2: Challenges and approaches to myokine discovery.

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Acknowledgements

M.W. and M.A.F. are supported by the National Health and Medical Research Council of Australia (NHMRC Project Grant APP1062436 to M.A.F and M.W; Research Fellowship APP11021168 to M.A.F.).

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Author notes

  1. Martin Whitham and Mark A. Febbraio: All authors contributed equally to this work.

Authors and Affiliations

  1. Diabetes & Metabolism Division, Cellular & Molecular Metabolism Laboratory, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010, New South Wales, Australia

    Martin Whitham & Mark A. Febbraio

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  1. Martin Whitham
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Correspondence to Mark A. Febbraio.

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Competing interests

M.A.F is a holder of patents for IC7, a gp130 receptor ligand.

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Glossary

VO2max

The term given to the maximal oxygen uptake; an indicator of aerobic capacity and cardiorespiratory fitness.

Myokine

A cytokine or peptide that is produced by skeletal muscle cells and subsequently released into the circulation to exert paracrine or endocrine effects.

Omics

A term given to the comprehensive biological assessment of entities with the suffix 'ome', such as the geneome, transcriptome and proteome (or proteinome).

Liquid chromatography tandem mass spectrometry

(LC–MS/MS). A technique used to identify proteins in complex mixtures via ionization and manipulation of the resultant ions to derive amino acid sequence information.

CRISPR

A gene editing tool that facilitates the establishment of genetically modified rodent models.

Adeno-associated viruses

Methods of gene transfer, in vivo, used to create transgenic overexpression mouse models in specific tissues.

Parabiosis

A mouse model of shared circulation, whereby surgical suturing initiates skin-to-skin contact of paired mice. After a period of 2 weeks, inflammation induces the development of microcirculation between mice so that the effect of a circulating factor from one animal can be assessed in the partner animal.

AMP-activated protein kinase

(AMPK). A kinase that is considered to be a master regulator of metabolism by sensing changes in AMP:ATP ratio.

PPARγ coactivator 1α

(PGC1α). A transcription factor that regulates genes involved in energy metabolism, of which there are at least four variants (PGC1α1 to PGC1α4).

PEGylation

Process of covalently adding repeating units of (polymerized) ethelene glycol to proteins with a view to improving stability, pharmacokinetics and therapeutic utility.

Fc fusion

Addition of the crystallizable fragment (Fc) domain of IgG molecules to therapeutic agents to improve pharmacokinetics and pharmacodynamics.

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Whitham, M., Febbraio, M. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat Rev Drug Discov 15, 719–729 (2016). https://doi.org/10.1038/nrd.2016.153

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