Toll-like receptor signalling in regenerative myogenesis: friend and foe

Abstract

Skeletal muscle regeneration in normal and diseased muscle is regulated by multiple factors and cells present in the injured muscle micro-environment. In addition to muscle progenitor cells, several immunocytes participate in the regenerative response. Among them, macrophages are one of the most important components of the immune response that governs the step-wise progression of muscle regeneration. The initial role of macrophages is to phagocytose muscle cell debris and later, through their transition to an anti-inflammatory phenotype, they promote regeneration. However, in several genetic muscle disorders, continuous muscle injury disrupts the balance between pro-inflammatory and anti-inflammatory macrophages, leading to an overall inflammatory milieu and inhibition of muscle regeneration. Accumulating evidence suggests that Toll-like receptor (TLR)-mediated signalling plays an important role in the regulation of macrophage phenotypes during regenerative myogenesis in response to both acute and chronic muscle injury. Here, we discuss the role of TLR signalling in regulating macrophage phenotypes and skeletal muscle regeneration in healthy and diseased muscle. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: Toll-like receptors; macrophages; muscular dystrophy; skeletal muscle regeneration.

FIGURE 1. Schematic representation of potential role of TLRs and macrophages in the regulation of muscle repair in response to acute versus chronic injury

(Left) Conventional activation of the inflammatory profile and subsequent muscle repair that follows single-hit injury in an orderly manner. Following acute injury, damaged muscle tissue secretes damage-associated molecular patterns (DMAPs) that activate toll-like receptor (TLR) signalling, which in turn induces the release of muscle cytokines and chemokines into the circulating plasma. Secreted cytokines and chemokines mediate the recruitment of monocytes from the bone marrow to the injury site. Upon entry into the muscle environment, monocytes differentiate into phagocytic pro-inflammatory M1 macrophages that are responsible for clearing of cellular debris and necrotic tissue. M1 macrophages also produce inflammatory cues that stimulate satellite cell activation and proliferation, after which they polarize to an anti-inflammatory M2 phenotype and promote myoblast differentiation and muscle formation, concluding the repair process. (Right) An atypical injury/regeneration programme characterized by a superimposed inflammatory response and recurring injury that perturbs the resolution of muscle repair in dystrophic muscle