PUBLICATION
Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
- Authors
- Volpatti, J.R., Endo, Y., Knox, J., Groom, L., Brennan, S., Noche, R., Zuercher, W.J., Roy, P., Dirksen, R.T., Dowling, J.J.
- ID
- ZDB-PUB-200403-208
- Date
- 2020
- Source
- eLIFE 9: (Journal)
- Registered Authors
- Noche, Ramil
- Keywords
- C. elegans, human biology, medicine, mouse, zebrafish
- MeSH Terms
-
- Pharmaceutical Preparations
- Neuromuscular Diseases/drug therapy
- Animals
- Ryanodine Receptor Calcium Release Channel/physiology*
- Caenorhabditis elegans
- RNA Interference
- Drug Discovery
- p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors*
- High-Throughput Screening Assays
- Small Molecule Libraries
- Mice
- Muscular Diseases/drug therapy*
- Muscle Fibers, Skeletal/drug effects
- Muscle Fibers, Skeletal/metabolism*
- Gene Knockout Techniques
- Calcium/metabolism*
- Zebrafish
- PubMed
- 32223895 Full text @ Elife
Citation
Volpatti, J.R., Endo, Y., Knox, J., Groom, L., Brennan, S., Noche, R., Zuercher, W.J., Roy, P., Dirksen, R.T., Dowling, J.J. (2020) Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline. eLIFE. 9:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping