Fork in the road: therapeutic and pathological actions for fibro-adipogenic progenitors following musculoskeletal injury

Musculoskeletal injuries are a substantial source of global disability through weakness and loss of function, which can be attributable, in part, to deficits in skeletal muscle quality. Poor muscle quality, resulting from fibrotic pathology or fatty infiltration, strongly predicts lower rates of patient recovery following injury and higher rates of re-injury. The cellular sources of fibrosis and fatty infiltration within skeletal muscle are mesenchymal fibro-adipogenic progenitors (FAPs), which are central effectors to support muscle homeostasis, regeneration and growth. However, following acute or chronic musculoskeletal injury, FAPs can promote fibro/fatty pathology within muscle that is likely to limit recovery and repair. Given their indispensable role within skeletal muscle, FAPs have emerged as a compelling cellular target to promote tissue recovery following acute and chronic injury. This review provides insight into the aetiology of FAP activity following various musculoskeletal injuries, in addition to signalling components that effect FAP differentiation. Contrasting pathology with therapeutic potential, insight into disease- and injury-specific FAP activation further cements their role as crucial effectors to improve muscle function and enhance patient outcomes. (Figure presented.).