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Doctor of Philosophy (PhD)
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Skeletal muscle is highly conserved among vertebrates and is essential for strength and locomotion. This tissue becomes integrated with the skeletal system via tendons at the myotendinous junction and with the nervous system at the neuromuscular junction. Both of these specialized junctions are rich in extracellular matrix, a protein scaffold that occupies the extracellular space of cells. Skeletal muscle is also highly plastic and can grow in size (hypertrophy) or lose mass (atrophy) in response to genetic or environmental cues. Muscle atrophy is found in individuals battling a number of neuromuscular conditions, including muscular dystrophy. Muscular dystrophies are a suite of incurable genetic diseases characterized by progressive muscle wasting and weakness. Secondary dystroglycanopathies are a subset of muscular dystrophies that result from mutations in genes that participate in Dystroglycan glycosylation. This process is necessary in order for muscle fibers to interact with the extracellular matrix and connect to nearby tendons and/or nerves. Patients battling secondary dystroglycanopathies experience a wide array of symptoms and severities, even when the molecular basis of their condition is identical. This prevents doctors and clinicians from providing patients and their families with accurate prognoses. Multiple roadblocks in our understanding of secondary dystroglycanopathies exist. We previously determined that improving muscle-extracellular matrix adhesion with NAD+ supplementation is sufficient to improve muscle structure in primary dystroglycanopathy. However, it is unknown whether this strategy is applicable to secondary dystroglycanopathies. It is also unknown how identical molecular variants of an allele can result in phenotypic variation among individuals with these conditions. Here, we leverage the zebrafish model system to address these gaps. We find that NAD+ supplementation prior to muscle development improves muscle structure in an established zebrafish model of secondary dystroglycanopathy, as well as myotendinous junctions and neuromuscular junctions. Additionally, we show that a new zebrafish model of secondary dystroglycanopathy exhibits phenotypic variation and plasticity throughout the first several days of life and is not improved by NAD+ supplementation. These studies highlight the importance of viewing secondary dystroglycanopathies as individual conditions at both the basic and clinical levels.
Bailey, Erin, "Neuromuscular Development and Phenotypic Variation in Zebrafish Models of Dystroglycanopathy" (2019). Electronic Theses and Dissertations. 3089.