Mechanism and treatment of RyR1-related skeletal muscle diseases

Type 1 ryanodine receptor (RyR1) is a Ca²⁺ release channel in the sarcoplasmic reticulum and plays an important role in excitation-contraction coupling. Genetic mutations in RyR1 cause various skeletal muscle diseases including malignant hyperthermia (MH) and central core disease. Since the main underlying mechanism of MH is overactive Ca²⁺-induced Ca²⁺ release (CICR) by gain-of-function of the RyR1 channel, inhibition of CICR is expected to be a promising treatment for these diseases. We have developed a novel high-throughput screening platform using time-lapse fluorescence measurement of Ca²⁺ in the endoplasmic reticulum to identify RyR1 inhibitors. By screening of a chemical compound library and subsequent structure expansion, we successfully developed Compound 1 (Cpd1) as a novel RyR1-selective inhibitor. Cpd1 effectively prevented or reversed the fulminant MH crisis by isoflurane anesthesia and heat stroke in mice carrying MH mutations. Thus, Cpd1 has the potential to be a promising new candidate for effective treatment of patients carrying RyR1 mutations.