Peripheral Nerve Injury and Denervation-Induced Sarcopenia with a Focus on Pharmacological Dual-Target Strategies

Peripheral nerve injury (PNI) causes rapid disruption of neuromuscular connectivity, leading to sarcopenia characterized by muscle wasting, mitochondrial dysfunction, and metabolic imbalance. Although calcium dysregulation and aberrant AMPK/mTOR signaling are known contributors, the molecular cascade linking nerve injury to muscle degeneration remains incompletely understood. This review explores pharmacological and molecular strategies to restore neuromuscular integrity after PNI. We focus on agents such as 4-aminopyridine (4-AP), a potassium channel blocker that enhances nerve conduction, and clemastine, an antihistamine that promotes Schwann cell-mediated remyelination. These compounds represent a potential dual approach to accelerating nerve repair while maintaining muscle viability. We also explore muscle-centered molecular strategies, focusing on pathways such as Forkhead box protein O (FOXO), Glycogen synthase kinase 3 beta (GSK-3β), signal transducer and activator of transcription 3 (STAT3), and TGF-β/Smad, which govern the balance between protein synthesis and degradation. Of note, most current studies suggest that phytochemicals derived from marine sources, including seaweed, may attenuate denervation-induced catabolism by modulating FOXO signaling and suppressing E3 ubiquitin ligase activity. Additionally, we highlight the critical crosstalk between motor neurons and skeletal muscle, mediated by neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Neurotrophin-3 (NT-3), which support both neuromuscular junction stability and axonal regrowth. By integrating insights from nerve biology and muscle physiology, this review outlines a therapeutic framework that targets both nerve regeneration and muscle preservation, an approach that effectively addresses nerve injury-induced sarcopenia effectively.