{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T09:51:24Z","timestamp":1773395484761,"version":"3.50.1"},"reference-count":26,"publisher":"American Physiological Society","issue":"5","funder":[{"DOI":"10.13039\/501100000038","name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2018-06324"],"award-info":[{"award-number":["RGPIN-2018-06324"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2019,11,1]]},"abstract":"<jats:p>\n                    Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC\n                    <jats:sup>\u2212<\/jats:sup>\n                    , a cystine\/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC\n                    <jats:sup>\u2212<\/jats:sup>\n                    activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC\n                    <jats:sup>\u2212<\/jats:sup>\n                    activation, as cotreatment with sulfasalazine (system xC\n                    <jats:sup>\u2212<\/jats:sup>\n                    inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. \u03b1-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC\n                    <jats:sup>\u2212<\/jats:sup>\n                    substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.\n                  <\/jats:p>","DOI":"10.1152\/ajpcell.00308.2019","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T15:03:26Z","timestamp":1568214206000},"page":"C894-C899","source":"Crossref","is-referenced-by-count":10,"title":["Statin administration activates system xC\n                    <sup>\u2212<\/sup>\n                    in skeletal muscle: a potential mechanism explaining statin-induced muscle pain"],"prefix":"10.1152","volume":"317","author":[{"given":"Irena A.","family":"Rebalka","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew W.","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda L.","family":"May","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Tarnopolsky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4974-4820","authenticated-orcid":false,"given":"Thomas J.","family":"Hawke","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00107.2011"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-005-5686-z"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00353.2003"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000001397"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1097\/MLR.0b013e3181c132ad"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2012.03.003"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.2.224"},{"key":"B8","first-page":"429","volume":"15","author":"Deichmann RE","year":"2015","journal-title":"Ochsner 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Journal of Physiology-Cell 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