AMPK regulates the maintenance and remodelling of the neuromuscular junction

Sean Y Ng; Andrew I Mikhail; Stephanie R Mattina; Salah A Mohammed; Shahzeb K Khan; Eric M Desjardins; Changhyun Lim; Stuart M Phillips; Gregory R Steinberg; Vladimir Ljubicic

doi:10.1016/j.molmet.2024.102066

AMPK regulates the maintenance and remodelling of the neuromuscular junction

Mol Metab. 2024 Nov 19:91:102066. doi: 10.1016/j.molmet.2024.102066. Online ahead of print.

Affiliations

¹ Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada.
² Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main St. W., Hamilton, ON, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, ON, Canada.
³ Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada. Electronic address: ljubicic@mcmaster.ca.

PMID: 39571900
DOI: 10.1016/j.molmet.2024.102066

Abstract

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.

Keywords: Acetylcholine receptors; Aging; Exercise; Mitochondria; PGC-1α.