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

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