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Duchenne muscular dystrophy (DMD) is a degenerative muscular disorder that affects 1 in 3,500 males and is characterized by progressive muscle weakness, loss of ambulation, and premature death. DMD is caused by an absence of the dystrophin protein. Dystrophin connects the actin cytoskeleton to the extracellular matrix, which stabilizes the sarcolemma during muscle contraction. In addition to the phenotypes of muscle degeneration, loss of ambulation, and premature death, other phenotypes of this disease include elevated calcium levels, oxidative stress, and mitochondrial damage. It is not precisely understood how the loss of dystrophin affects the molecular mechanisms that lead to degeneration. We are investigating gene expression in dystrophic C. elegans that genetically model Duchenne muscular dystrophy through mutations in the worm dystrophin homolog (dys-1). Under high exertion exercise, the dys-1(eg33) strain of dystrophic worms recapitulates the most severe features of DMD. However, a dystrophic strain with a similarly missense mutation near the eg33 loci (dys-1(cx18)), displays a significantly less severe phenotype. RNA seq data from muscle specific tissue identified several genes that have differential expression between these two dystrophic strains. We have identified differentially expressed genes with known roles in calcium handling, muscle contractile ability, and mitochondrial function. We are presently using RNA interference as a screen to identify genes that decrease calcium levels in muscle. Genes that show decreased calcium levels when silenced will then be further studied to see how this manipulation impacts locomotor ability and longevity. This approach has the potential to identify therapeutic targets sensitive to manipulation and help improve the quality of life of individuals suffering with Duchenne muscular dystrophy.
Tamrazi, Monica, "The Search For Genes That Prevent Muscle Degeneration Associated With Duchenne Muscular Dystrophy" (2021). Biology. 15.