Deciphering Statin-Induced Muscle Symptoms: Mechanisms and Therapeutic Insights

Project Summary Statin therapy is widely prescribed for the management of cardiovascular diseases, yet statin-associated muscle symptoms (SAMSs) frequently lead to therapy discontinuation. Our study aims to elucidate the underlying mechanisms of SAMSs and explore potential therapeutic interventions. We hypothesize that statin-induced muscle weakness is mediated through ryanodine receptor 1 (RyR1) calcium leakage, exacerbated by the RyR1- T4706M mutation. We have access to muscle tissue and other samples from a patient who carries this RyR1- T4706M mutation and is profoundly intolerant of all statins. We further have a mouse model based on this patient’s genotype. Using cryo-electron microscopy, electrophysiological recordings, in vitro assays, and genetic mouse models, we will identify the binding sites of commonly used statins on RyR1, evaluate their effects on muscle function, and assess the potential benefits of RyR1 stabilization with ARM210 in preventing statin- induced muscle weakness. This research holds promise for identifying novel therapeutic strategies to mitigate SAMSs and improve patient tolerance of statin therapy.