Myostatin-driven muscle hypertrophy: a double-edged sword in muscle physiology

Abstract Myostatin (MSTN), a pivotal regulator of skeletal muscle homeostasis, belongs to the TGF-β family and functions as a potent inhibitor of muscle hypertrophy. While physiological muscle hypertrophy is a normal adaptive response, dysregulated or excessive hypertrophy often resulting from myostatin pathway disruption can contribute to rare pathological conditions. As a key molecular checkpoint in myogenesis, myostatin modulates the Akt/mTOR pathway, satellite cell dynamics, and ubiquitin-proteasome-mediated protein degradation. Loss-of-function mutations in the MSTN gene disrupt this inhibitory axis, resulting in excessive muscle growth, a phenomenon extensively studied in both animal models and rare human cases. Myostatin inhibition has emerged as a therapeutic strategy for muscle-wasting disorders such as Duchenne muscular dystrophy (DMD), sarcopenia, and cachexia. However, the systemic ramifications of long-term myostatin blockade necessitate a deeper understanding of its role in muscle physiology and metabolic regulation. This review synthesizes current advancements in myostatin signaling, its interplay with myogenic regulatory factors, therapeutic inhibitors under clinical investigation, and potential translational challenges. While targeting myostatin holds clinical promise, optimizing its therapeutic index requires a precise balance between muscle anabolism and functional integrity.