Sema4A Protects Against Muscle Atrophy and Promotes Repair by Regulating Intracellular Metabolic Signalling

BACKGROUND: Skeletal muscle atrophy is a debilitating condition associated with diverse diseases and clinical interventions. Although triggers such as glucocorticoid excess or direct muscle injury disrupt the balance between protein homeostasis and tissue repair, the upstream molecular signals that actively preserve muscle integrity remain largely unknown. Semaphorin 4A (Sema4A) is a Class IV transmembrane semaphorin traditionally recognized for its roles in neural development and immune regulation; however, its function in skeletal muscle maintenance has not been explored. METHODS: We first examined Sema4A expression in established models of muscle catabolism. Subsequently, adeno-associated virus (AAV)-mediated Sema4A restoration was employed to evaluate its therapeutic potential in both dexamethasone-induced atrophy and acute injury mouse models. Mechanistic studies were performed in C2C12 myotubes using gain- and loss-of-function approaches. RESULTS: N/g B.W., p = 0.0422). We identified Plexin B2 (Plxnb2) as the functional receptor mediating these effects. At the molecular level, Sema4A signalling suppressed FoxO3a nuclear translocation (FoxO3a positive cells: vector-Dex 27.99% vs. OE-Sema4A-Dex 12.49%, p < 0.05), thereby inhibiting the expression of key atrogenes, while simultaneously reactivating the PI3K-AKT-mTOR anabolic pathway. This reprogramming of intracellular metabolic signalling was further associated with the establishment of a reparative immune microenvironment, a process potentially modulated by muscle-derived factors such as Gdf15. CONCLUSIONS: Our study identifies Sema4A as a novel protective regulator that mitigates muscle atrophy and enhances regeneration through a dual mechanism: restoring intracellular anabolic signalling and fostering a proregenerative immune niche. These findings highlight Sema4A as a promising therapeutic target for the treatment of muscle-wasting disorders.