Abstract
Regeneration of injured skeletal muscles relies on a tightly controlled chain of cellular and molecular events. We show that appropriate levels of S100B protein are required for timely muscle regeneration after acute injury. S100B released from damaged myofibers and infiltrating macrophages expands the myoblast population, attracts macrophages and promotes their polarization into M2 (pro-regenerative) phenotype, and modulates collagen deposition, by interacting with RAGE (receptor for advanced glycation end-products) or FGFR1 (fibroblast growth factor receptor 1) depending on the muscle repair phase and local conditions. However, persistence of high S100B levels compromises the regeneration process prolonging myoblast proliferation and macrophage infiltration, delaying M1/M2 macrophage transition, and promoting deposition of fibrotic tissue via RAGE engagement. Interestingly, S100B is released in high abundance from degenerating muscles of mdx mice, an animal model of Duchenne muscular dystrophy (DMD), and blocking S100B ameliorates histopathology. Thus, levels of S100B differentially affect skeletal muscle repair upon acute injury and in the context of muscular dystrophy, and S100B might be regarded as a potential molecular target in DMD.
Highlights
Upon injury skeletal muscles initiate a repair process leading to tissue regeneration
We show here that: 1) early after acute muscle injury released S100B expands the myoblast population, attracts macrophages to damage sites and promotes M1/M2 macrophage switch in a RAGE-dependent manner; 2) during the M2 macrophage phase S100B promotes M1/M2 macrophage switch via stimulation of RAGE and/or FGFR1 activity depending on local conditions; 3) infiltrating macrophages transiently express and release S100B that contributes to the regeneration process together with myofiber-released S100B; and 4) if present in high abundance at damage sites S100B sustains the M1 macrophage phase via excess RAGE engagement thereby compromising regeneration and promoting fibrotic tissue deposition
We found that (1) the S100B neutralizing antibody used throughout was specific to S100B (Fig. S1a); (2) anti-S100B antibody reduced S100B’s ability to inhibit the expression of the late myogenic differentiation marker, myosin heavy chain (MyHC)[18] (Fig. S1b); and (3) when added to myoblasts cultured in differentiation medium without added S100B, this antibody stimulated MyHC expression consequent to neutralization of the S100B normally present in FBS18 (Fig. S1b)
Summary
Upon injury skeletal muscles initiate a repair process leading to tissue regeneration. In a chronic muscle disease setting such as Duchenne muscular dystrophy (DMD) unrestricted liberation of DAMPs from damaged myofibers fuels infiltration with M1 macrophages, which leads to persistent degeneration/regeneration cycles causing progressive depletion of the muscle stem cell pool, chronic inflammation and fibrosis[14]. We show here that: 1) early after acute muscle injury released S100B expands the myoblast population, attracts macrophages to damage sites and promotes M1/M2 macrophage switch in a RAGE-dependent manner; 2) during the M2 macrophage phase S100B promotes M1/M2 macrophage switch via stimulation of RAGE and/or FGFR1 activity depending on local conditions; 3) infiltrating macrophages transiently express and release S100B that contributes to the regeneration process together with myofiber-released S100B; and 4) if present in high abundance at damage sites (e.g. in muscular dystrophy) S100B sustains the M1 macrophage phase via excess RAGE engagement thereby compromising regeneration and promoting fibrotic tissue deposition. Levels of S100B dictate its effects in acute and persistent muscle injury
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