Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
- The Hospital for Sick Children, Canada
- University of Toronto, Canada
- University of Rochester, United States
- University of North Carolina at Chapel Hill, United States
- University of Rochester School of Medicine and Dentistry, United States
Abstract
Ryanodine receptor type I-related myopathies (RYR1-RMs) are a common group of childhood muscle diseases associated with severe disabilities and early mortality for which there are no available treatments. The goal of this study is to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a discovery pipeline using nematode, zebrafish, and mammalian cell models. We first performed large-scale drug screens in C. elegans which uncovered 74 hits. Targeted testing in zebrafish yielded positive results for two p38 inhibitors. Using mouse myotubes, we found that either pharmacological inhibition or siRNA silencing of p38 impaired caffeine-induced Ca2+ release from wild type cells while promoting intracellular Ca2+ release in Ryr1 knockout cells. Lastly, we demonstrated that p38 inhibition blunts the aberrant temperature-dependent increase in resting Ca2+ in myotubes from an RYR1-RM mouse model. This unique platform for RYR1-RM therapy development is potentially applicable to a broad range of neuromuscular disorders.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source files are available for all figures.
Article and author information
Author details
Funding
Muscular Dystrophy Association
- Robert T Dirksen
- James J Dowling
RYR1 Foundation
- Robert T Dirksen
- James J Dowling
Canadian Institutes of Health Research (363863)
- Robert T Dirksen
- James J Dowling
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All zebrafish experiments were performed in accordance with all relevant ethical regulations, specifically following the policies and guidelines of the Canadian Council on Animal Care and an institutionally reviewed and approved animal use protocol (#41617). No additional ethical approval was required for our experiments with the invertebrate nematode worm C. elegans.
Copyright
© 2020, Volpatti et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
eLife 9:e52946.
https://doi.org/10.7554/eLife.52946
