Reduced IGF signaling prevents muscle cell death in a Caenorhabditis elegans model of muscular dystrophy
Edited by Iva Greenwald, Columbia University, New York, NY, and approved October 15, 2013 (received for review May 9, 2013)
Significance
Duchenne muscular dystrophy (DMD) affects 1 in 3,500 live male births and is a fatal degenerative muscle disease with no known cure. The primary cause of DMD is muscle necrosis due to the loss of the dystrophin protein in the muscle membrane. However, the underlying cellular mechanisms that lead to cell death are not known. Using Caenorhabditis elegans as a model of muscular dystrophy, we show that whereas loss of dystrophin function is a primary cause of muscle degeneration, muscle cell death is greatly influenced by age-dependent, intrinsically variable cellular environments. We further show that reduction of insulin-like growth factor 1 signaling, which rejuvenates the cellular environments, helps to protect against muscle cell death caused by loss of dystrophin function.
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.
Acknowledgments
We thank Dr. Garsin for sharing a daf-2 RNAi clone, and J. Pierce-Shimomura and L. Abraham for critically reading the manuscript. Some strains were provided by the CGC, which is funded by National Institutes of Health Office of Research Infrastructure Programs (P40OD01440). This work was supported by the NIH Grant R21NS077018 (to H.K.).
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Published online: November 4, 2013
Published in issue: November 19, 2013
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Acknowledgments
We thank Dr. Garsin for sharing a daf-2 RNAi clone, and J. Pierce-Shimomura and L. Abraham for critically reading the manuscript. Some strains were provided by the CGC, which is funded by National Institutes of Health Office of Research Infrastructure Programs (P40OD01440). This work was supported by the NIH Grant R21NS077018 (to H.K.).
Notes
This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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