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.
Highlights
The ryanodine receptor type I (RyR1) is a calcium release channel located in the terminal cisternae of the sarcoplasmic reticulum (SR) in skeletal muscle
During excitation-contraction coupling (ECC), RyR1 is activated by the voltage sensing L-type calcium channel dihydropyridine receptor (DHPR), located in the transverse tubule (T-tubule) membrane
RYR1 mutations are associated with a wide range of clinical phenotypes, collectively referred to as RYR1-related myopathies (RYR1-RM), that can include wheelchair and ventilator dependence, and dynamic symptoms such as exercise induced myalgias, heat stroke, and malignant hyperthermia (Klein et al, 2012; Amburgey et al, 2013; Snoeck, et al, 2015; Jungbluth et al, 2016; Matthews et al, 2018)
Summary
The ryanodine receptor type I (RyR1) is a calcium release channel located in the terminal cisternae of the sarcoplasmic reticulum (SR) in skeletal muscle. During excitation-contraction coupling (ECC), RyR1 is activated by the voltage sensing L-type calcium channel dihydropyridine receptor (DHPR), located in the transverse tubule (T-tubule) membrane. RYR1 mutations are associated with a wide range of clinical phenotypes, collectively referred to as RYR1-related myopathies (RYR1-RM), that can include wheelchair and ventilator dependence, and dynamic symptoms such as exercise induced myalgias, heat stroke, and malignant hyperthermia (Klein et al, 2012; Amburgey et al, 2013; Snoeck, et al, 2015; Jungbluth et al, 2016; Matthews et al, 2018). Despite their relatively high prevalence and associated morbidities, there are currently no approved pharmacological therapies for patients with RYR1-RM
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