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 <i>C. elegans</i> 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 Ca<sup>2+</sup> release from wild type cells while promoting intracellular Ca<sup>2+</sup> release in <i>Ryr1</i> knockout cells. Lastly, we demonstrated that
p38 inhibition blunts the aberrant temperature-dependent increase in resting Ca<sup>2+</sup> 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.