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Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of dystrophin, responsible for connecting actin to the sarcolemma and transferring force into the extracellular matrix. In humans, DMD presents at a young age, resulting in developmental delays, muscle necrosis, increased sarcoplasmic calcium, loss of ambulation, and early death. Current animal models do not model the severity of DMD without the addition of sensitizing mutations. Thus, it remains elusive if increased sarcoplasmic calcium observed in dystrophic muscles follows or leads the mechanical insults caused by the muscle’s disrupted contractile machinery. This knowledge has important implications for patients, as physiotherapeutic treatments may either help or exacerbate symptoms, depending on how dystrophic muscles differ from healthy ones.
We observe that sarcoplasmic calcium dysregulation in dys-1 worms precedes overt structural phenotypes and can be mitigated by silencing calmodulin. Recently, we showed that burrowing dystrophic (dys-1) worms recapitulate many salient phenotypes of DMD. Here, we report dys-1 worms display early pathogenesis and increased lethality. To learn how dystrophic musculature responds to altered physical activity, we cultivated dys-1 animals in environments requiring either high intensity or high frequency muscle exertion during locomotion. We find that several muscular parameters (such as size) improve with increased activity. However, longevity in dystrophic animals was negatively associated with muscular exertion regardless of the duration of the effort. The high degree of phenotypic conservation between dystrophic worms and humans provides a unique opportunity to gain insights into DMD’s underlying pathology and to assess potential treatment strategies.
Hughes, Kiley, "Muscular Exertion Exacerbates Degeneration In A C. Elegans Model Of Duchenne Muscular Dystrophy" (2021). Biology. 19.