{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:30:06Z","timestamp":1791199806731,"version":"4.2.0"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Skeletal Muscle"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>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<jats:sup>2+<\/jats:sup>) 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, \u2018YS\u2019) 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<jats:sub>2<\/jats:sub>), sustained muscle contractures, rhabdymyolysis, and elevated core body temperature.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We assessed the ability of simvastatin to induce a hypermetabolic response in the YS mice using indirect calorimetry and to alter Ca<jats:sup>2+<\/jats:sup> release via RyR1 in isolated flexor digitorum brevis (FDB) fibers from WT and YS mice using fluorescent Ca<jats:sup>2+<\/jats:sup> indicators. We also tested the ability of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) to protect against the simvastatin effects.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>An acute dose of simvastatin triggers a hypermetabolic response in YS mice. In isolated YS muscle fibers, simvastatin triggers an increase in cytosolic Ca<jats:sup>2+<\/jats:sup> levels by increasing Ca<jats:sup>2+<\/jats:sup> leak from the sarcoplasmic reticulum (SR). With higher simvastatin doses, a similar cytosolic Ca<jats:sup>2+<\/jats:sup> increase occurs in wild type (WT) muscle fibers. Pre-treatment of YS and WT mice with AICAR prevents the response to simvastatin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>A mutation in RyR1 associated with malignant hyperthermia increases susceptibility to an adverse response to simvastatin due to enhanced Ca<jats:sup>2+<\/jats:sup> 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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/2044-5040-3-22","type":"journal-article","created":{"date-parts":[[2013,9,3]],"date-time":"2013-09-03T16:14:29Z","timestamp":1378224869000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Mice with RyR1 mutation (Y524S) undergo hypermetabolic response to simvastatin"],"prefix":"10.1186","volume":"3","author":[{"given":"Mark","family":"Knoblauch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adan","family":"Dagnino-Acosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,9,3]]},"reference":[{"issue":"12","key":"84_CR1","doi-asserted-by":"publisher","first-page":"858","DOI":"10.7326\/0003-4819-150-12-200906160-00009","volume":"150","author":"T Joy","year":"2009","unstructured":"Joy T, Hegele R: Narrative review: statin-related myopathy. 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