Key result
An acute dose of simvastatin triggers a hypermetabolic response characterized by significantly increased oxygen consumption in mice with a RyR1 mutation, which is prevented by AICAR.
Why the study?
Does simvastatin induce a hypermetabolic response in mice with the RyR1 Y524S mutation, and can AICAR prevent this effect?
Does simvastatin induce a hypermetabolic response in mice with the RyR1 Y524S mutation, and can AICAR prevent this effect?
Mice with a RyR1 mutation associated with malignant hyperthermia exhibit increased susceptibility to simvastatin-induced hypermetabolic response and calcium leak, which can be prevented by AICAR.
May signal statin hypermetabolic risk in RyR1 mutation carriers; leaves open AICAR translation to human myopathy prevention.
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 (Ca2+) 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 (VO2), 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 Ca2+ release via RyR1 in isolated flexor digitorum brevis (FDB) fibers from WT and YS mice using fluorescent Ca2+ 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 Ca2+ levels by increasing Ca2+ leak from the sarcoplasmic reticulum (SR). With higher simvastatin doses, a similar cytosolic Ca2+ 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 Ca2+ 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.
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Knoblauch et al. (2013) studied Statin-induced myopathy susceptibility. Simvastatin vs. Vehicle (DMSO) was evaluated on Peak oxygen consumption (VO2) indicating a hypermetabolic response (p=<0.001). An acute dose of simvastatin triggers a hypermetabolic response characterized by significantly increased oxygen consumption in mice with a RyR1 mutation, which is prevented by AICAR.
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