Fibro-Adipogenic Progenitors require autocrine IGF-I in homeostatic and regenerating skeletal muscle

Fibro-Adipogenic Progenitors (FAPs) are mesenchymal stem cells that are vital for muscle homeostasis and regeneration but produce fibrosis and intramuscular fat under pathological conditions. Insulin-like Growth Factor-I (IGF-I) is a key regulator of muscle repair, satellite cell activity, macrophage polarization, and extracellular matrix (ECM) remodeling. We generated inducible FAP-specific Igf1 deficient (FID) mice to determine the necessity of FAP IGF-I. After BaCl2 injury, FID mice exhibited impaired muscle regeneration, with fewer Pax7+ cells, increased macrophage accumulation, smaller fibers, reduced ECM, and depressed FAP proliferation. Following glycerol injury, FID muscles exhibited reduced adipocyte accumulation. Primary FAPs isolated from injured FID muscles had blunted growth, upregulation of immune-regulatory genes and downregulation of ECM and cell proliferation genes, with delayed responses to fibrogenic and to adipogenic media. FAP property alterations were already present in homeostatic muscle, indicated by scRNASeq, with decreased indices of protein translation and ECM production as well as increased markers of senescence, confirmed in vivo and in vitro. Overall, FAP IGF-I is a critical autocrine factor, with further paracrine consequences for muscle regenerative capacity.