Date of Award
Doctor of Philosophy (PhD)
School of Biological Sciences
Andres G Vidal-Gadea
Duchenne muscular dystrophy (DMD) is an x-linked degenerative disease that affects one out of every 3,500 males. This disease is produced by loss of function mutations in the dystrophin gene that results in the absence of the dystrophin protein from muscles and other tissues. Loss of dystrophin leads to progressive muscle weakness, loss of ambulation, and premature death. At the cellular level, patients present with increased sarcoplasmic calcium, loss of sarcomeric integrity, and mitochondrial damage. There is no cure for DMD. Understanding the progression of the disease and developing effective treatments has been hampered by lack of animal models able to recapitulate the disease at both the genotypic and phenotypic levels. Our lab recently showed that dystrophic C. elegans nematodes (dys-1) raised in burrowing environments recapitulate key phenotypes associated with dystrophic patients. My doctoral work focuses on understanding the progression of Duchenne muscular dystrophy, and in identifying molecular pathways that may be amenable to therapeutic interventions. My dissertation evaluates the extent to which dystrophic nematodes model Duchenne muscular dystrophy; contributes to our understanding of the pathophysiology of this disorder; and investigates different potential therapeutic avenues that might help stop or slow down the progression of this disease. In chapter I, I develop a method for modeling neurodegenerative diseases in C. elegans by altering their culture conditions to closely match what worms experience in nature. By having worms burrow in three dimensions through agar, rather than crawl around on an agar plate as is typically done in the lab, muscular exertion is increased and dystrophin mutants show locomotor defects. In chapter II I further characterize our dystrophic animals. I find that burrowing dystrophic worms undergo severe muscle degeneration, are slower in speed, do not develop normally, have swollen mitochondria, and die prematurely. Like human patients, dystrophic worms have excess levels of calcium. Furthermore, I found that while calcium release from the sarcoplasmic reticulum occurs normally, calcium clearance following a contraction cycle is slower. I found that deficits are already apparent in freshly-hatched larvae. These include excess calcium and slower development. During normal muscle function, calcium is important in both force generation but also in proprioceptive feedback. In chapter IV I discuss the mechanoreceptor pezo-1. Here, we focus on both the expression and function of different isoforms of pezo-1, which is the building blocks for an ongoing project exploring the role of long pezo-1 isoforms in body wall muscle and production of normal locomotion. Understanding how healthy muscles function and adapt is necessary to uncovering how muscles fail in disease states such as DMD. Dystrophic nematodes model known Duchenne muscular dystrophy pathology with a high degree of genotypic and phenotypic faithfulness which, coupled with its great experimental amenability, makes dystrophic worms a useful vehicle to understand this disorder and develop new therapeutics able to slow degeneration and improve the lives of Duchenne muscular dystrophy patients.
Hughes, Kiley, "Understanding the Pathogenesis of Duchenne Muscular Dystrophy Using a Caenorhabditis Elegans Model" (2022). Theses and Dissertations. 1529.