Macrophages in Skeletal Muscle Dystrophies, An Entangled Partner

Abstract

While skeletal muscle remodeling happens throughout life, diseases that result in its dysfunction are accountable for many deaths. Indeed, skeletal muscle is exceptionally capable to respond to stimuli modifying its homeostasis, such as in atrophy, hypertrophy, regeneration and repair. In particular conditions such as genetic diseases (muscular dystrophies), skeletal muscle's capacity to remodel is strongly affected and undergoes continuous cycles of chronic damage. This induces scarring, fatty infiltration, as well as loss of contractibility and of the ability to generate force. In this context, inflammation, primarily mediated by macrophages, plays a central pathogenic role. Macrophages contribute as the primary regulators of inflammation during skeletal muscle regeneration, affecting tissue-resident cells such as myogenic cells and endothelial cells, but also fibro-adipogenic progenitors, which are the main source of the fibro fatty scar. During skeletal muscle regeneration their function is tightly orchestrated, while in dystrophies their fate is strongly disturbed, resulting in chronic inflammation. In this review, we will discuss the latest findings on the role of macrophages in skeletal muscle diseases, and how they are regulated.

Keywords: Macrophage; inflammation; muscle dystrophy; repair; skeletal muscle.

Fig. 1

Temporal expression of macrophage and inflammatory markers. After damage, infiltrated monocytes differentiate into macrophages, up-regulate CD11c, CD11b, F4/80, and CX3CR1 (top graph) and express pro-inflammatory markers such as Ly-6C, CCR2, iNOs, and Cox-2 (middle graph). After 1-2 days in the tissue, they downregulate pro-inflammatory markers and start to express anti-inflammatory proteins such as CD206, CD163, and Arginase 1 (bottom graph).

Fig. 2

Macrophages orchestrate muscle-resident cell behaviour during tissue repair. Left panel: after injury, Ly-6C+ macrophages secrete CCL3, NO, TNFα and IL-1β, clear fibro-adipogenic progenitors (FAPs) from the tissue, and support myogenic cell proliferation. Once skewed to an anti-inflammatory profile, macrophage produce IL-6, GDF3, TGFβ, and VEGF, which participate into the support of the myogenic program and myofiber growth. Macrophage content within the tissue returns to basal around 2 weeks after damage by either re-circulation or local apoptosis. Right panel: in case of repeated trauma, the number of macrophages present in the tissue rises, which could be due to continuous infiltration, or to local proliferation. Both Ly-6C+ and Ly-6C–macrophages are present within the tissue, which causes the accumulation of both pro- and anti-inflammatory cytokines in the damaged area. FAPs are activated, differentiate into fibroblast and adipocytes and myogenesis is delayed.

Fig. 3

mdx-macrophage specific functions. Via the production of many cytokines and proteins, macrophages present in mdx muscle are able to simultaneously stimulate and inhibit various cellular processes such as monocyte infiltration, satellite cell (SC) proliferation, myofiber growth, fibro-adipogenic progenitor (FAP) proliferation and differentiation.