Reduced IGF signaling prevents muscle cell death in a Caenorhabditis elegans model of muscular dystrophy

Abstract

Duchenne muscular dystrophy, a fatal degenerative muscle disease, is caused by mutations in the dystrophin gene. Loss of dystrophin in the muscle cell membrane causes muscle fiber necrosis. Previously, loss-of-function mutations in dys-1, the Caenorhabditis elegans dystrophin ortholog, were shown to cause a contractile defect and mild fiber degeneration in striated body wall muscle. Here, we show that loss of dystrophin function in C. elegans results in a shorter lifespan and stochastic, age-dependent muscle- cell death. Reduction of dystrophin function also accelerated age-dependent protein aggregation in muscle cells, suggesting a defect in proteostasis. Both muscle cell death and protein aggregation showed wide variability among the muscle cells. These observations suggest that muscle cell death in dys-1 mutants is greatly influenced by cellular environments. Thus, the manipulation of the cellular environment may provide an opportunity to thwart the cell death initiated by the loss of dystrophin. We found that reduced insulin-like growth factor (IGF) signaling, which rejuvenates the cellular environment to protect cells from a variety of age-dependent pathologies, prevented muscle cell death in the dys-1 mutants in a daf-16-dependent manner. Our study suggests that manipulation of the IGF signaling pathways in muscle cells could be a potent intervention for muscular dystrophy.