Mice with RyR1 mutation (Y524S) undergo hypermetabolic response to simvastatin

BACKGROUND: Statins are widely used drugs for the treatment of hyperlipidemia. Though relatively safe, some individuals taking statins experience rhabdymyolysis, muscle pain, and cramping, a condition termed statin-induced myopathy (SIM). To determine if mutations in the skeletal muscle calcium (Ca(2+)) release channel, ryanodine receptor type 1 (RyR1), enhance the sensitivity to SIM we tested the effects of simvastatin, the statin that produces the highest incidence of SIM in humans, in mice with a mutation (Y524S, ‘YS’) in RyR1. This mutation is associated with malignant hyperthermia in humans. Exposure of mice with the YS mutation to mild elevations in environmental temperature produces a life-threatening hypermetabolic response (HMR) that is characterized by increased oxygen consumption (VO(2)), sustained muscle contractures, rhabdymyolysis, and elevated core body temperature. METHODS: We assessed the ability of simvastatin to induce a hypermetabolic response in the YS mice using indirect calorimetry and to alter Ca(2+) release via RyR1 in isolated flexor digitorum brevis (FDB) fibers from WT and YS mice using fluorescent Ca(2+) indicators. We also tested the ability of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) to protect against the simvastatin effects. RESULTS: An acute dose of simvastatin triggers a hypermetabolic response in YS mice. In isolated YS muscle fibers, simvastatin triggers an increase in cytosolic Ca(2+) levels by increasing Ca(2+) leak from the sarcoplasmic reticulum (SR). With higher simvastatin doses, a similar cytosolic Ca(2+) increase occurs in wild type (WT) muscle fibers. Pre-treatment of YS and WT mice with AICAR prevents the response to simvastatin. CONCLUSIONS: A mutation in RyR1 associated with malignant hyperthermia increases susceptibility to an adverse response to simvastatin due to enhanced Ca(2+) release from the sarcoplasmic reticulum, suggesting that RyR1 mutations may underlie enhanced susceptibility to statin-induced myopathies. Our data suggest that AICAR may be useful for treating statin myopathies.