Abstract
Skeletal muscle atrophy emerges from intertwined neuromuscular and metabolic failures, in which neuromuscular junction destabilization, excitation contraction coupling defects, and mitochondrial dysfunction collectively intensify calcium dysregulation and drive the accumulation of reactive oxygen and nitrogen species (RONS), reinforcing proteolytic and catabolic signaling programs. To integrate recent evidence on the neuromuscular redox interface and highlight therapeutic strategies that target these interdependent drivers of atrophy. RONS-mediated activation of NF-κB and FOXO pathways accelerates ubiquitin proteasome and autophagy lysosome degradation, leading to motor unit loss. Stem cell therapies (satellite cells, MSCs, and iPSC progenitors) seek to restore regenerative potential but face hurdles in engraftment and reinnervation. Gene-based interventions, including antioxidant gene delivery, Nrf2 activation, RNA modulators, and CRISPR editing, offer new avenues but remain limited by safety and delivery barriers. Bioengineering platforms such as hydrogels, decellularized scaffolds, and extracellular vesicles provide architectural, trophic, and immunomodulatory support. Translational progress requires rigorous safety pipelines, mechanistic biomarkers of motor unit recovery, and modular combination regimens that integrate cells, genes, scaffolds, and rehabilitative input. By aligning neuromuscular biology with redox control, emerging strategies hold promise to rebuild innervated, fatigue-resistant muscle across acquired and genetic atrophy syndromes.