Neuromuscular Junction as a Molecular Target in Sarcopenia: Mechanisms, Therapeutic Strategies, and Future Directions

Sarcopenia is a progressive loss of skeletal muscle mass and strength that significantly contributes to frailty and disability in older adults. Traditionally considered a consequence of myofiber atrophy and impaired protein turnover, recent evidence highlights neuromuscular junction (NMJ) degeneration as an early and critical event in the pathogenesis of this condition. Structural and functional changes at the NMJ, including fragmentation of acetylcholine receptor clusters, motor neuron loss, and disruption of agrin–muscle-specific kinase (MuSK) signaling, impair neuromuscular transmission and accelerate muscle decline. This review synthesizes current understanding of NMJ biology, its age-related deterioration, and emerging therapeutic strategies aimed at preserving synaptic integrity. We discuss pharmacological approaches that target presynaptic neurotransmitter synthesis, stabilize the synaptic cleft, and enhance postsynaptic receptor clustering, as well as interventions that activate Schwann and satellite cells to restore regenerative capacity. Adjunctive therapies such as antioxidants, mitochondrial protectants, and metabolic modulators complement NMJ-specific drugs by mitigating oxidative stress and inflammation. Translational insights underscore the importance of NMJ-specific biomarkers, such as circulating c-terminal agrin fragment-22 (CAF22), and advanced imaging modalities to facilitate early detection and personalized interventions. Future directions focus on multimodal regimens that combine NMJ-targeted agents with exercise, nutrition, and digital health tools, supported by computational analytics for precision care. By integrating molecular, systemic, and lifestyle strategies, NMJ-focused therapies offer a promising approach to delaying the progression of sarcopenia and improving functional independence in aging populations. Continued interdisciplinary research and mechanistically informed clinical trials are crucial for translating these advances into effective treatments.