RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth

Abstract

Adult skeletal muscle is a plastic tissue that can adapt its size to workload. Here, we show that RhoA within myofibers is needed for overload-induced hypertrophy by controlling satellite cell (SC) fusion to the growing myofibers without affecting protein synthesis. At the molecular level, we demonstrate that RhoA controls in a cell autonomous manner Erk1/2 activation and the expressions of extracellular matrix (ECM) regulators such as Mmp9/Mmp13/Adam8 and macrophage chemo-attractants such as Ccl3/Cx3cl1. Their decreased expression in RhoA mutants is associated with ECM and fibrillar collagen disorganization and lower macrophage infiltration. Moreover, matrix metalloproteinases inhibition and macrophage depletion in controls phenocopied the altered growth of RhoA mutants while having no effect in mutants showing that their action is RhoA-dependent. These findings unravel the implication of RhoA within myofibers, in the building of a permissive microenvironment for muscle hypertrophic growth and for SC accretion through ECM remodeling and inflammatory cell recruitment.

Selective ablation of Nfix in macrophages attenuates muscular dystrophy by inhibiting fibro‐adipogenic progenitor‐dependent fibrosis

“…Indeed, inhibition of ROCK accelerates muscle regeneration after acute injury [56,57]. In overload conditions, RhoA loss in myofibers impairs hypertrophy by decreasing the number of myonuclei/myofibers, due to less fusion of SCs with myofibers [58]. In our two murine models, ROCK inhibition did not modify the number of SCs expressing Nfix, but we observed a decrease in the number of SCs per mm 2 that is consistent with previous studies [56,57].…”

Differences in muscle satellite cell dynamics during muscle hypertrophy and regeneration

“…Compared to the process of muscle regeneration, the mechanism regulating MuSC dynamics under muscle loading (such as a resistance training) has not been well investigated. However, recent studies have analyzed the mechanisms underlying MuSC proliferation and cell–cell communication in loaded muscles [ 9 , 10 , 12 , 13 ]. We briefly summarize the process of muscle regeneration and load-dependent muscle hypertrophy according to key factors underlying MuSC behaviors and discuss six differences in MuSC dynamics and cell–cell interactions between the regeneration and hypertrophy processes.…”

“…Compared to the roles of macrophages in regenerating muscle, macrophage functions in loaded muscle are limited, although recent studies have revealed the roles of macrophages in mechanically loaded muscle at the molecular level [ 10 ]. Peck et al reported that macrophages promote extracellular matrix (ECM) remodeling by secreting matrix metallopeptidase 14 (Mmp14) [ 13 ], and their data suggest that leukemia inhibitory factor (LIF) from myofibers stimulates Mmp14 expression in macrophages.…”

“…Peck et al reported that macrophages promote extracellular matrix (ECM) remodeling by secreting matrix metallopeptidase 14 (Mmp14) [ 13 ], and their data suggest that leukemia inhibitory factor (LIF) from myofibers stimulates Mmp14 expression in macrophages. Noviello et al demonstrated that macrophages are essential for muscle hypertrophy because macrophage depletion by clodronate liposomes inhibited myofiber growth [ 10 ]. The authors also revealed that RhoA signaling in loaded myofibers induces the expression of the chemokine Ccl3/Cx3cl1, which recruits macrophages into the loaded muscle.…”

Monocyte–Macrophage Lineage Cell Fusion

“…Cell fusion is a multistep process involving the acquisition of fusion competence, cell movement, adhesion to the substrate, interaction between fusing partners, and eventually, the fusion of cell membranes [ 43 ]. These steps require a profound rearrangement of the cell cytoskeleton, especially actin filaments, orchestrated by small GTPases Rac-1 and RhoA pathways [ 42 , 64 , 70 , 89 , 90 , 91 ]. Before fusion, cells must adhere to place their membranes in close contact.…”