Neuromuscular Junction Degeneration in Skeletal Muscle Atrophy: Disease-Specific Mechanisms, Evidence-Informed Stratification, and Therapeutic Windows

Skeletal muscle atrophy involves not only the loss of muscle mass and fiber size, but also a significant decline in contractile performance. Force decline often occurs before visible fiber atrophy, suggesting that early defects in neuromuscular transmission might trigger or exacerbate the wasting process. Therefore, we argue that neuromuscular junction (NMJ) degeneration is not a universal, conserved pathway across all atrophy syndromes. Instead, it should be viewed as a stage- and disease-specific event, with its actual contribution varying based on specific evidence. To explore this, we compare NMJ maintenance and degeneration across a broad spectrum of conditions, ranging from primary neuromuscular diseases (like denervation and motor neuron disorders) to systemic states such as aging, cachexia, and metabolic or respiratory diseases. Based on this, we propose a framework to evaluate NMJ involvement by timing, lesion type, and reversibility, drawing on diverse evidence from morphological, electrophysiological, and biomarker studies. Crucially, this approach distinguishes primary synaptic disorders from systemic conditions where NMJ damage acts merely as a secondary modifier. Ultimately, aligning specific molecular lesions with practical intervention windows will help refine patient stratification and guide the design of more targeted NMJ therapies.