Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

Abstract

Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1α expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1α-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1α-BNP axis and thereby provide novel targets for therapeutic approaches.

Hormones, Metabolism and the Benefits of Exercise

“…Similar to these observations in SCs, muscles may also have a memory in terms of the post-exercise inflammatory response: in human volunteers, MCP-1 levels as well as CD68 + macrophages were higher two days after a repeated bout compared to the first bout of exercise (Deyhle et al 2015). While the mechanisms underlying this finding remain enigmatic, similar exacerbated macrophage activation is observed upon elevation of BNP by PGC-1α in exercised muscle (Furrer et al 2017). Moreover, in muscles overexpressing PGC-1α, a larger area of cardiotoxin-damaged muscle is covered by macrophages and thus undergoing regeneration (Dinulovic et al 2016a).…”

“…PGC-1α induces the transcription of secreted phosphoprotein 1 (SPP1), which in turn is involved in the recruitment of macrophages and activation of epithelial cells to ensure functional neovascularization (Rowe et al 2014b). In the context of acute exercise, PGC-1α controls the expression of the B-type natriuretic peptide (BNP), which promotes macrophage activation in a paracrine manner (Furrer et al 2017). While M1 macrophage activation is resolved more rapidly in damaged PGC-1α-overexpressing muscles (Dinulovic et al 2016a), the mechanisms by which muscle PGC-1α affects infiltration and polarization in this context are still unclear.…”

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…Interestingly, exercise-induced PGC-1a upregulation also plays an immunomodulatory role in skeletal muscle by influencing cytokine expression; a PGC-1a-dependent Btype natriuretic peptide (BNP) production in myofibers induces M2 polarization, playing an anti-inflammatory and pro-repair role. Therefore, BNP might be considered a novel PGC-1a-dependent myokine mediating the cross-talk between tissue resident MF and skeletal muscle, as observed in mice (96). In addition, the myokine irisin-upregulated by exercise-induced PGC-1a-also suppresses inflammation and stimulates M2 polarization in vitro (74).…”

Regulation of skeletal muscle recovery

“…Diet-induced thermogenesis represents metabolic oxygen cost for processing of ingested nutrients. Green and colleagues [125] indeed reported enhanced DIT in emphysematous COPD patients, but this was not confirmed by other authors [149,150], independently of BMI [151]. These differences may be due to different test meal composition and portion size.…”

“…This likely reflects the important role for macrophages in the regulation of satellite cell function [57,58]. Interestingly, secreted factors from the muscle fiber regulate macrophage activation, and potentially macrophage polarization [149]. As such, macrophages may play a mediating role in muscle fiber -satellite cell cross-talk, even in the absence of muscle trauma.…”