From Fixed Lineage to Dynamic States: Fibro-Adipogenic Progenitors in Skeletal Muscle Regeneration, Fibrosis, and Fibrofatty Degeneration

Skeletal muscle repair depends on coordinated interactions among muscle stem cells, immune cells, extracellular matrix, and resident stromal cells. A key stromal population, fibro-adipogenic progenitors (FAPs), has attracted considerable attention. Yet FAPs are not a fixed mesenchymal lineage. They form a plastic, heterogeneous compartment with context-dependent functional states that shift with injury stage, anatomical site, disease, and species. Understanding what drives this plasticity is essential. This review examines how biochemical, inflammatory, mechanical, and epigenetic signals shape FAP states. We synthesize evidence from multiple species, including mouse, human, bovine, porcine, and camel muscle systems. Four regulatory modules are considered: TGF-β/PDGFRα signaling and immune crosstalk, canonical and non-canonical Wnt pathways, epigenetic regulation, and extracellular matrix mechanotransduction. Through these pathways, FAPs adopt distinct functional programs. These include homeostatic maintenance, reparative support, fibrogenic activation, adipogenic differentiation, inflammatory response, and senescence. Each program differentially influences muscle stem cell function and tissue remodeling outcomes. These programs reflect context-dependent FAP states, not a uniform lineage with fixed functions. Several concepts require clarification. We emphasize that fibrogenic and adipogenic programs can be differentially regulated yet coexist within diseased muscle, and that pathological FAP states may retain context-dependent reversibility. These insights clarify the constraints on cross-species translation and inform the design of stage-matched, context-appropriate, or combinatorial FAP-directed therapeutic strategies for muscle disease.