AMPK SIGNALLING IN THE PERIPHERAL NEUROMUSCULAR SYSTEM

Abstract

Inherited or acquired abnormalities at any level of the peripheral neuromuscular system (i.e., alpha-motor neuron, skeletal muscle, neuromuscular junction) results in neurotransmission failure and impaired muscular function and mobility, which are common characteristics of neuromuscular diseases (NMDs) and aging. As such, exploring the intricate mechanisms underlying neuromuscular biology is crucial for informing about future therapeutics. AMP-activated protein kinase (AMPK) is emerging as a key mediator of neuromuscular health. Thus, the purpose of my dissertation was to elucidate the role of AMPK in the peripheral neuromuscular system in health and disease. In studies 1 and 2, we demonstrated that AMPK activity and related pathways such as mitochondrial dynamics and autophagy were perturbed in skeletal muscle of myotonic dystrophy type 1 (DM1) and spinal muscular atrophy (SMA) mice, which are among the most prevalent NMDs in adults and infants, respectively. Interestingly, AMPK stimulation via acute exercise induced a favourable signalling cascade that targeted mitochondrial plasticity in DM1 and SMA animals, while urolithin A administration induced autophagy and augmented mitochondrial health in SMA patient-derived skeletal muscle cells. Lastly, for study 3, we found that developmental or adult-onset ablation of skeletal muscle-specific AMPK triggered deleterious effects at the neuromuscular junction. We also observed that AMPK signalling is not required for mediating the physiological or cellular benefits of endurance exercise training. Moreover, long-term treatment of aged mice with a direct AMPK activator induced remarkable improvements in skeletal muscle mass, endurance and strength that were underpinned with enhanced mitochondrial health, reduced fibrosis, and overall better muscle quality. Collectively, my PhD research supports the hypothesis that AMPK is at the nexus of neuromuscular health and provokes investigations on the therapeutic potential of AMPK in other NMDs.