ABSTRACT: Fibro-Adipogenic Progenitors (FAPs) are mesenchymal progenitor cells vital for muscle homeostasis and regeneration, but they also produce fibrosis and differentiate into intramuscular fat under pathological conditions. Insulin-like Growth Factor-I (IGF-I), a key regulator of muscle repair, influences satellite cell activity, macrophage polarization, and extracellular matrix (ECM) remodeling. Although FAPs are a major source of IGF-I in muscle, its specific role remains unclear. Thus, we generated inducible FAP-specific Igf1 knockout mice (FID mice) to determine the necessity of the FAP IGF-I source. After acute BaCl2 injury, FID mice exhibited impaired muscle regeneration, characterized by fewer Pax7+ cells, increased CD68+ macrophage accumulation, smaller fibers with lower proportions of EmbMHC+ fibers, and reduced ECM content compared to controls. FAP proliferation was impaired, with fewer total and Ki67+ FAPs in regenerating muscles from FID mice. Following glycerol injury, muscles from FID mice exhibited reduced adipocyte accumulation. To probe the autocrine role of FAP IGF-I, we isolated FAPs from muscles 3 days post-injury. Primary FAPs isolated from FID mice had blunted growth, accompanied by upregulation of immune-regulatory genes and downregulation of ECM and cell proliferation genes by RNASeq. Additionally, cultured FID FAPs had delayed differentiation and sustained PDGFRα expression in response to TGF-β, as well as impaired adipocyte differentiation in adipogenic media. Finally, FID FAPs entered a senescent state shortly after Cre recombination, showing high β-Gal expression in vivo and in vitro, and suppression of IGF-IR and IGF-I-dependent pathways. Taken together, our findings demonstrate that IGF-I derived from FAPs is a critical autocrine factor, with its absence leading to impaired function of FAPs for maintenance of muscle regenerative capacity
