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. / Dissertation / Doctor of Philosophy (PhD) / The neuromuscular junction (NMJ) plays a vital role in maintaining muscle function and countering aging and neuromuscular disorders. This thesis investigated the role of AMP-activated protein kinase (AMPK) in neuromuscular biology during conditions of health and disease. We conducted various experiments involving genetic modifications, drug treatments, and exercise. First, we determined that AMPK is necessary to maintain the NMJ during aging. Stimulation of AMPK with a potent activator, MK-8722 (MK), led to elevated NMJ-related gene expression. We then shifted our focus to the most prevalent neuromuscular disorder, Duchenne Muscular Dystrophy (DMD). Our results showed that MK activated AMPK in dystrophic mice, prompting us to further investigate the long-term effects of daily treatment in a pre-clinical DMD model. Repeated MK treatment significantly improved neuromuscular function and reduced the symptoms of DMD. Together, our comprehensive investigation demonstrates the critical role of AMPK in shaping neuromuscular plasticity during healthy and diseased conditions.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/28955 |
| Date | January 2023 |
| Creators | Ng, Sean |
| Contributors | Ljubicic, Vladimir, Kinesiology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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