Muscle-Organ Crosstalk: Focus on Immunometabolism

Abstract

Skeletal muscle secretes several hundred myokines that facilitate communication from muscle to other organs, such as, adipose tissue, pancreas, liver, gut, and brain. The biological roles of myokines include effects on e.g., memory and learning, as well as glucose and lipid metabolism. The present minireview focuses on recent developments showing that exercise-induced myokines are involved in immunometabolism of importance for the control of e.g., tumor growth and chronic inflammation. In this review, immunometabolism is discussed as the non-immune related pathologies leading to an immune response and some degree of inflammation, which promotes metabolic abnormalities.

Keywords: cancer; cytokines; diabetes; exercise; metabolism; physical activity.

FIGURE 1

I Irisin and Cathepsin B enhance BDNF production and thereby hippocampal neurogenesis. IL-6 inhibits appetite and stimulates lipolysis. IL-6 also plays a role in decreasing the amount of visceral fat. IL-6, irisin and meteorin-like are involved in turning white adipose tissue into a brown phenotype. IL-15 retards skin aging. IL-6, decorin, FGF-2 and IGF-1 positively influence bone formation. Myostatin negatively influence bone formation. Musclin, LIF, IL-4, IL-6, IL-7, and IL-15 are involved in mediating muscle hypertrophy, whereas myostatin obstructs muscle hypertrophy. IL-6 and BDNF stimulate AMPK activation and hence fat oxidation. IL-6 e stimulates glucose uptake and hepatic glucose output during exercise. IL-6 induces the expression of GLP-1 by the L cells of the intestine leading to enhanced insulin secretion. IL-6 exerts anti-inflammatory effects by inhibiting TNF production and by stimulating IL-1ra and IL-10 production. IL-6 enhances cortisol production, leading to neutrocytosis and lymphopenia. FSTL-1 has beneficial effects on endothelial function and revascularization of atherosclerotic blood vessels. Osteoprotegerin, angiogenin, and IL-6 possess beta-cell protective actions against inflammatory cytokines. AMPK, 5’-AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor; FGF-2, fibroblast growth factor 2; FGF-21, fibroblast growth factor 21; FSTL-1, follistatin-related protein 1; GLP-1, glucagon-like peptide 1; IGF-1, insulin-like growth factor I; IL-1ra, IL-1 receptor antagonist; LIF, leukemia inhibitory factor; TGF-β, transforming growth factor β; TNF, tumor necrosis factor. Adapted with permission from Severinsen and Pedersen (2020).

FIGURE 2

(1) Exercising muscles release multiple compounds known as myokines. Several of these have been shown to affect cancer cell proliferation in culture, and some, including interleukin-6, slow tumor growth in mice. (2) Exercise stimulates an increase in levels of the stress hormones epinephrine and norepinephrine, which can both act directly on tumors and stimulate immune cells to enter the bloodstream. (3) Epinephrine also stimulates natural killer cells to enter circulation. (4) In mice, interleukin-6 appears to direct natural killer cells to home in on tumors. Reprinted with permission from Pedersen (2020). Illustrator: Scott Leighton. (5) Epinephrine and norepinephrine along with some myokines can inhibit tumor growth.