Resident mesenchymal progenitor cells require autocrine IGF-I in homeostatic and regenerating skeletal muscle

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal stromal cells essential for homeostasis and regeneration but can produce fibrosis or intramuscular fat in pathological conditions. Insulin-like growth factor-I (IGF-I) regulates regeneration through actions on muscle fibers, satellite cells, macrophages, and extracellular matrix (ECM) remodeling but has multiple sources. To assess the role of FAP-derived IGF-I, we generated inducible FAP-specific Igf1-deficient (FID) mice. Following BaCl₂ injury, FID muscles displayed impaired regeneration, with smaller fibers, fewer Pax7⁺ and MyoD⁺ cells, increased CD68⁺ macrophages, decreased collagen, and suppressed FAP proliferation. After glycerol-induced injury, FID muscles had reduced fat. Primary FID FAPs displayed blunted proliferation, upregulated immune-regulatory genes, and downregulated ECM and growth genes, with delayed fibrogenic and adipogenic differentiation. scRNA-seq of homeostatic muscle revealed reduced protein translation and ECM indices alongside increased senescence markers in FID samples. Taken together, FAP IGF-I is critical for FAP function, with direct and indirect impact on muscle regeneration.