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Objective: The molecular mechanisms underlying the maintenance and adaptability of the neuromuscular junction (NMJ) remain poorly understood. This study aimed to investigate the role of AMP-activated protein kinase (AMPK) as a key regulator of NMJ stability and plasticity. Method: A comprehensive, multifaceted approach was employed, integrating genetic, physiological, and pharmacological methodologies to elucidate the role of skeletal muscle AMPK in modulating the neuromuscular synapse. Results: Our findings reveal an increased abundance of AMPK transcripts within the NMJ and an age-associated decline in AMPK activity and synapse-specific mitochondrial gene expression. Young mice null for skeletal muscle AMPK displayed a neuromuscular phenotype akin to aged animals. Pharmacological AMPK stimulation facilitated its localization in subsynaptic myonuclei, preceded the induction of several NMJ-related transcripts, and enhanced myotube acetylcholine receptor clustering. Exercise-induced AMPK activation in mouse muscle elicited a broad NMJ-related gene response, consistent with human exercise data. Conclusions: These findings highlight a critical role for AMPK in the maintenance and remodeling of the NMJ, highlighting its potential as a therapeutic target for age-related and neuromuscular disorders.