Intracellular calcium dysregulation precedes muscle decline in C. elegans modeling Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of the protein dystrophin. In humans, DMD has early onset, causes developmental delays, muscle necrosis, loss of ambulation, and early death. Current animal models have been challenged by their inability to model the early onset and severity of the disease. Thus it remains unresolved if increased sarcoplasmic calcium observed in dystrophic muscles follows or leads the mechanical insults caused by the muscles disrupted contractile machinery. This knowledge has important applications for patients, as potential physiotherapeutic treatments may either help or exacerbate symptoms, depending on how dystrophic muscles differ from healthy ones. Recently we showed how burrowing dystrophic (dys-1) C. elegans recapitulate many salient phenotypes of DMD, including loss of mobility and muscle necrosis. Here we report dys-1 worms display early pathogenesis, including dysregulated sarcoplasmic calcium, and increased lethality. Sarcoplasmic calcium dysregulation in dys-1 worms precedes overt structural phenotypes (e.g. mitochondrial, and contractile machinery damage) and can be mitigated by silencing calmodulin expression. To learn how dystrophic musculature responds to altered physical activity, we cultivated dys-1 animals in environments requiring high amplitude, or high frequency of 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 the etiology of the disease, as well as the initial assessment of potential treatment strategies.\n\nSIGNIFICANCEDuchenne muscular dystrophy is a degenerative disease affecting tens of thousands of people in the US alone. Much remains unknown about the disease, including the chain of events that links the loss of dystrophin to muscle death, or the extent to which exercise might be able to protect degenerating muscles. We used the nematode C. elegans to show that sarcoplasmic calcium dysregulation takes place in dystrophic muscles long before other overt signs of damage manifest. When placed in assays that altered muscular activity by increasing either contraction frequency or amplitude, we observed several metrics associated with muscular repair increase. However, no treatment positively affected the life expectancy of dystrophic animals.