The Role of AMPK in Neuromuscular Health and Disease

Abstract

The neuromuscular junction (NMJ) exhibits an extraordinary capacity for adaptation and plasticity throughout an individual's lifespan. This remarkable adaptability assumes a central role in safeguarding optimal neuromuscular function and counteracting neurodegenerative processes commonly associated with aging and prevalent neuromuscular disorders. The plasticity of the NMJ is under the influence of its cellular constituents, including the ⍺-motoneuron and the innervated muscle fiber. Among the diverse array of regulatory molecules, AMP-activated protein kinase (AMPK) plays a pivotal role in governing the phenotype of these cellular components, thereby potentially contributing to synaptic modifications. To explore the regulatory role of AMPK on the NMJ phenotype, we undertook a comprehensive investigation encompassing transgenic, pharmacologic, and physiologic manipulations of this kinase. In Study 1, we investigated the significance of skeletal muscle AMPK during aging, revealing its necessity in preserving NMJ integrity. Moreover, we observed that pharmacological and physiological activation of AMPK result in an enhanced synaptic gene profile in young animals, suggesting its role in NMJ modulation. Building upon these insights, we validate the stimulatory effects of a pan-AMPK activator, MK-8722 (MK), in the context of a prevalent neuromuscular disorder, Duchenne Muscular Dystrophy (DMD). Our investigations demonstrated that MK effectively evoked AMPK activation and downstream signaling in dystrophic muscle, providing the experimental foundations our third study. Here, we assess of the chronic effects of daily MK treatment in a pre-clinical DMD model and revealed significant improvements in mitochondrial health, neuromuscular function, and a reduction in muscle fibrosis and fatigue. Taken together, these findings support a critical role of AMPK in neuromuscular plasticity and highlight the kinase as a promising therapeutic target for muscular dystrophy.