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.

中文翻译：

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使用多物种发现途径鉴定与RYR1相关的肌病的药物修饰剂

Ryanodine受体I型相关性肌病（RYR1-RMs）是与严重残疾和早期死亡相关的常见儿童期肌肉疾病，目前尚无可用的治疗方法。这项研究的目的是确定RYR1-RMs的新治疗靶标。为此，我们开发了使用线虫，斑马鱼和哺乳动物细胞模型的发现管道。我们首先在秀丽隐杆线虫中进行了大规模的药物筛选，发现了74个匹配项。斑马鱼的靶向测试对两种p38抑制剂产生了积极的结果。用小鼠肌管中，我们发现，无论是药理学抑制或siRNA沉默p38的受损咖啡因诱导的Ca的²⁺从野生型细胞释放，同时促进细胞内Ca ²⁺释放在Ryr1基因敲除细胞。最后，我们证明RYR1-RM小鼠模型的肌管中p38抑制作用使静止的Ca ^2+的温度依赖性异常升高变钝。RYR1-RM治疗开发的独特平台可能适用于广泛的神经肌肉疾病。