AMPK regulates the maintenance and remodelling of the neuromuscular junction

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. 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. 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. 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. [Display omitted] •We used genetic and pharmacological approaches to define the role of AMPK at the NMJ.•Old mice displayed reduced AMPK activity and synapse-specific mitochondrial transcripts.•Young AMPK mKO mice exhibited a neuromuscular phenotype similar to aged animals.•Active AMPK localized in subsynaptic nuclei and preceded NMJ transcript expression.•These data reveal a new role for AMPK in the maintenance and plasticity of the NMJ.