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Review
. 2022 May;18(5):273-289.
doi: 10.1038/s41574-022-00641-2. Epub 2022 Mar 18.

Exerkines in health, resilience and disease

Lisa S Chow  1 , Robert E Gerszten  2 , Joan M Taylor  3 , Bente K Pedersen  4 , Henriette van Praag  5 , Scott Trappe  6 , Mark A Febbraio  7 , Zorina S Galis  8 , Yunling Gao  8 , Jacob M Haus  9 , Ian R Lanza  10 , Carl J Lavie  11 , Chih-Hao Lee  12 , Alejandro Lucia  13   14   15 , Cedric Moro  16   17 , Ambarish Pandey  18 , Jeremy M Robbins  2 , Kristin I Stanford  19 , Alice E Thackray  20 , Saul Villeda  21 , Matthew J Watt  22 , Ashley Xia  23 , Juleen R Zierath  24   25 , Bret H Goodpaster  26 , Michael P Snyder  27
Affiliations
Review

Exerkines in health, resilience and disease

Lisa S Chow et al. Nat Rev Endocrinol. 2022 May.

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.

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Conflict of interest statement

Competing interests

The other authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. The systemic effects of exercise.
a | Organs and tissues that can serve as source of exerkines and that are directly affected by exercise. b | Exercise results in profound health benefits, including reductions in the presence or severity of certain diseases, as well as increases in healthspan, longevity and resilience. T2DM, type 2 diabetes mellitus.
Fig. 2 |
Fig. 2 |. Examples of exerkines that affect the cardiometabolic system.
Exerkines released after exercise into the systemic circulation (see TABLE 3 for tissue sources, detailed effects and relevant references), including proteins (blue lines), metabolites (yellow circles) and extracellular vesicles (green circles), affect the cardiometabolic system. The effects are wide-ranging and systemic. In the cardiovascular system, exerkines enhance vascularization and angiogenesis, as well as improve blood pressure, endothelial function and overall fitness, resulting in cardioprotection. In adipose tissue, exerkines increase fatty acid uptake, enhancing lipolysis, thermogenesis and glucose metabolism. In the liver, exerkines enhance glucose metabolism and fatty acid uptake. In skeletal muscle, exerkines enhance muscle formation, maintenance and repair, glucose uptake, lipid oxidation, mitochondrial biogenesis and muscle capillarization. In the pancreas, exerkines enhance cell viability and influence insulin secretion. Commonly described exerkines are noted. 12,13-diHOME, 12,13-dihydroxy-9Z-octadecenoic acid; BAIBA, β-aminoisobutyric acid; FGF21, fibroblast growth factor 21; GDF15, growth and differentiation factor 15; HSP72, heat shock protein 72; METRNL, meteorin-like; SDC4, syndecan 4; SPARC, secreted protein acidic and cysteine rich; TGFβ2, transforming growth factor-β2; VEGF, vascular endothelial growth factor.
Fig. 3 |
Fig. 3 |. Effects of exercise on the immune system.
Exercise induces lipid oxidation, mitochondrial biogenesis and local injury, which stimulates exerkine release into the circulation to influence the immune system. See Supplementary Table 1 for detailed effects and relevant references. These include proteins (blue lines), metabolites (yellow circles) and extracellular vesicles (green circles), which have a multitude of effects on the immune system (generically represented by a monocyte). Acutely, exercise increases cytokines such as circulating levels of transforming growth factor β1 (TGFβ1) and IL-6 relative to the resting state. This change results in acute inflammation, characterized by increases in tumour necrosis factor (TNF) and IL-6. Once the acute exercise-induced effects have diminished, an increase in anti-inflammatory cytokines (such as IL-10 and IL-1 receptor antagonist (IL-1RA)) occurs in response to the acute inflammatory response. Chronic training is associated with a reduction in systemic and tissue inflammation, as characterized by lower circulating levels of TNF and IL-6 in the resting state, relative to sedentary individuals. Reduced insulin resistance and tumour growth has been attributed to the effects of chronic training on decreasing systemic and/or tissue inflammation.
Fig. 4 |
Fig. 4 |. Effects of exercise on the nervous system.
Exercise stimulates the production of exerkines from tissues, such as skeletal muscle, adipose tissue or the liver, to affect the nervous system. See Supplementary Table 1 for detailed effects and relevant references. These exerkines are released into the circulation and include proteins (blue lines), metabolites (yellow circles) and extracellular vesicles (green circles), which have a multitude of purported effects on the nervous system. These effects include increasing production of brain-derived neurotrophic factor (BDNF), enhancing neurogenesis (even in adults), cognition, mood and synaptic plasticity. The extent to which exerkines cross the blood-brain barrier to exert their effects remains unknown, symbolized by the question mark. There is uncertainty with GDF15, as symbolized by the question mark, as pharmacological GDF15 inhibits appetite and reduces activity, whereas physiological induction of GDF15 by exercise does not. Commonly described exerkines are noted. FGF21, fibroblast growth factors 21; GDF15, growth and differentiation factor 15; GPLD1, glycosylphosphatidylinositol-specific phospholipase D1.
See this image and copyright information in PMC

Comment in

  • Reply to 'Lactate as a major myokine and exerkine'.
    Chow LS, Gerszten RE, Taylor JM, Pedersen BK, van Praag H, Trappe S, Febbraio MA, Galis ZS, Gao Y, Haus JM, Lanza IR, Lavie CJ, Lee CH, Lucia A, Moro C, Pandey A, Robbins JM, Stanford KI, Thackray AE, Villeda S, Watt MJ, Xia A, Zierath JR, Goodpaster BH, Snyder M. Chow LS, et al. Nat Rev Endocrinol. 2022 Nov;18(11):713. doi: 10.1038/s41574-022-00726-y. Nat Rev Endocrinol. 2022. PMID: 35915255 No abstract available.
  • Lactate as a major myokine and exerkine.
    Brooks GA, Osmond AD, Arevalo JA, Curl CC, Duong JJ, Horning MA, Moreno Santillan DD, Leija RG. Brooks GA, et al. Nat Rev Endocrinol. 2022 Nov;18(11):712. doi: 10.1038/s41574-022-00724-0. Nat Rev Endocrinol. 2022. PMID: 35915256 No abstract available.

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