[
International Worm Meeting,
2021]
Duchenne muscular dystrophy is an x-linked disorder that claims the lives of one in every 3,500 males. The disease is caused by mutations that result in the absence of the dystrophin protein from the membrane of muscle cells where it plays important structural and signaling roles. Without dystrophin, muscle-generated forces are unable to safely exit the cell. This results in cellular injuries, most consequentially to the plasma membrane. Individuals become wheelchair bound between seven to twelve years of age, and typically die in their late teens to twenties. While there is some variability in the rate and the severity of the degeneration, patients suffer a plethora of debilitating symptoms associated with progressive muscle degeneration and loss. There is no cure for Duchenne muscular dystrophy. Lack of progress and understanding of this disorder is largely the result of animal models failing to recapitulate both the genetic and phenotypic severity observed in humans. However, understanding the molecular events that link loss of dystrophin to muscle death remains of paramount importance. This knowledge will help us identify targets amenable to intervention and offer hope to more than one million individuals suffering this disease across the world. Our lab uses dystrophic nematodes to generate insights into the pathophysiology of Duchenne muscular dystrophy, and to identify novel therapeutic avenues. By harnessing the natural burrowing behavior of C. elegans we demonstrated that dystrophic worms recapitulate key aspects of the disease to a greater extent than those observed in most research models currently used. We report a study of the embryonic development of dystrophic animals. Here we show that sarcoplasmic calcium dysregulation associated with dystrophic muscles starts early during development. Furthermore, a suppressor screen, and a comparison of dystrophic strains displaying different severity, both point to muscle calmodulin as a potential therapeutic target. Dystrophic worms provide a unique opportunity for studying the mechanism by which dystrophic cells degenerate, and to identify intervention avenues. To validate findings obtained using our dystrophic animals we are presently developing a human muscle culture system.