FIGURE 4.

Fibro-adipogenic progenitors as central drivers of muscle pathology and fibro-fatty infiltration. Skeletal muscles have high regenerative capabilities after a single round of injury, which progressively diminishes following chronic damage. Hence, chronic injury primes the tissue into a state of progressive degeneration. In homeostasis, a high proportion of fibro-adipogenic progenitors are perivascular cells and remain quiescent. Injury activates FAPs and induces their expansion and differentiation into several mesenchymal lineages, including activated fibroblasts, adipocytes, and bone-like cells. Activated FAPs and their lineage derived fibroblasts produce increased amounts of extracellular matrix (ECM), leading to connective tissue hyperplasia and poorer outcomes for patients. In several traumas and pathology, the adipogenic differentiation of FAPs also impairs muscle function and integrity. Muscle degeneration associates with an increased number of FAPs, activated TGF-β signaling and enhanced fibrosis. Chondrogenic and osteogenic FAP differentiation are not depicted to simplify the cartoon.