Skeletal muscle in spinal muscular atrophy: Critical insights from pathogenesis to therapeutic strategies

AbstractSpinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein. While SMA was originally viewed as a pure motor neuron disease, it is currently considered a multi-system disorder in which skeletal muscle plays a pathogenic role. Muscular defects, such as impaired myogenesis and mitochondrial dysfunction, contribute to pathogenesis partly independently of denervation. Accumulating evidence suggests that the SMN deficit impairs muscle development from the earliest stages of fetal life, with delayed myotube maturation and modification of the expression of myogenic regulatory factors. This leads to pathology characterized by selective fiber atrophy, metabolic disturbances, and severe involvement of axial and intercostal musculature with relative sparing of the diaphragm. Furthermore, despite the revolutionary therapeutic effects of nusinersen, risdiplam, and onasemnogene abeparvovec, skeletal muscle abnormalities remain frequent, particularly in symptomatic patients, highlighting the need for muscle-directed therapies. Of the current candidate approaches, myostatin inhibition, targeting a negative regulator of muscle mass, is the most clinically advanced, while other strategies such as mitochondrial protection remain at earlier developmental stages. Work with neuromuscular models and stem cell-derived organoids continues to shed light on the SMN-mediated interactions between muscle and nerve. Collectively, these findings indicate that skeletal muscle is both a key driver of SMA pathology and an essential target for novel therapies.