The ESCRT protein CHMP5 controls skeletal muscle homeostasis and coordinates myeloid cell-mediated tissue repair

Abstract

Abstract Macrophages promote skeletal muscle homeostasis by participating in crosstalk with satellite cells, fibroadipogenic precursors, and myofibers that drives regeneration after injury. Dysregulation of this crosstalk contributes to conditions like myopathy, inefficient wound healing, and sarcopenia. Despite their central role in muscle homeostasis and regeneration, the tissue-intrinsic mechanisms that coordinate the recruitment and activity of these macrophages are poorly understood. In this study, we investigated how skeletal muscle homeostasis is regulated by the ESCRT protein CHMP5. CHMP5 was initially characterized as a member of the ESCRT family of proteins that coordinate membrane scission events in eukaryotic cells. However, recent studies by us and others have revealed non-canonical roles for CHMP5 wherein CHMP5 promotes the stability of client proteins required for cellular differentiation and cell fate decisions in hematopoietic and non-hematopoietic tissues. Using an in vitro model of myogenesis, we found that CHMP5 knockdown impaired the differentiation of C2C12 myoblasts into myotubes. Furthermore, when wild-type BMDMs were cocultured with CHMP5-knockdown C2C12 myoblasts, they failed to polarize into M2-like macrophages. In vivo, mice with muscle-specific CHMP5 heterozygous deletion (CHMP5 hetmice) displayed diminished myeloid cell presence in muscle following cardiotoxin-induced injury. 12 days post-injury, histologic and flow cytometric analyses of muscles from CHMP5 hetmice revealed less regenerative progress than littermate controls. These data suggest a critical function for CHMP5 in promoting muscle homeostasis both in the steady state and in the context of injury and inflammation. Supported in part by intramural funding from the National Cancer Institute, T32 GM007250, T32 NS077888-08, and NIH R01AI143992-03.