{"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":1791199806836,"version":"4.2.0"},"reference-count":56,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health \/ National Heart, Lung, and Blood Institute","award":["R01HL145473"],"award-info":[{"award-number":["R01HL145473"]}]},{"name":"National Institutes of Health \/ National Institute of Diabetes, Digestive & Kidney Diseases","award":["R01DK118240"],"award-info":[{"award-number":["R01DK118240"]}]},{"name":"National Institutes of Health \/ National Heart, Lung, and Blood Institute","award":["R01HL142903"],"award-info":[{"award-number":["R01HL142903"]}]},{"name":"National Institutes of Health \/ National Heart, Lung, and Blood Institute","award":["R01HL140934"],"award-info":[{"award-number":["R01HL140934"]}]},{"name":"National Institutes of Health \/ National Institute of Neurological Disorders and Stroke","award":["R01NS114570"],"award-info":[{"award-number":["R01NS114570"]}]},{"name":"National Institutes of Health \/ National Institute of Arthritis and Musculoskeletal and Skin Diseases","award":["R01AR070194"],"award-info":[{"award-number":["R01AR070194"]}]},{"name":"National Institutes of Health \/ National Heart, Lung, and Blood Institute","award":["R25HL156002R25"],"award-info":[{"award-number":["R25HL156002R25"]}]},{"name":"National Institutes of Health \/ National Institute of Neurological Disorders and Stroke","award":["R25NS076445"],"award-info":[{"award-number":["R25NS076445"]}]},{"name":"National Institutes of Health \/ National Heart, Lung, and Blood Institute","award":["P01 HL164319"],"award-info":[{"award-number":["P01 HL164319"]}]},{"name":"National Institutes of Health \/ National Heart, Lung, and Blood Institute","award":["T32 HL120826"],"award-info":[{"award-number":["T32 HL120826"]}]},{"name":"National Institutes of Health \/ National Institute of Arthritis and Musculoskeletal and Skin Diseases","award":["R01AR085078"],"award-info":[{"award-number":["R01AR085078"]}]},{"name":"National Institutes of Health \/ National Institute of Arthritis and Musculoskeletal and Skin Diseases","award":["R01AR078000"],"award-info":[{"award-number":["R01AR078000"]}]},{"name":"National Institutes of Health \/ National Heart, Lung, and Blood Institute","award":["R01HL178501"],"award-info":[{"award-number":["R01HL178501"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,15]]},"abstract":"<jats:p>Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)\/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.<\/jats:p>","DOI":"10.1172\/jci194490","type":"journal-article","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T19:00:54Z","timestamp":1765738854000},"source":"Crossref","is-referenced-by-count":4,"title":["Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation"],"prefix":"10.1172","volume":"135","author":[{"given":"Gunnar","family":"Weninger","sequence":"first","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haikel","family":"Dridi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Reiken","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Groom","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Leigh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Tchagou","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Luna-Figueroa","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco C.","family":"Miotto","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anetta","family":"Wronska","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Dirksen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Marks","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2001.tb00172.x"},{"issue":"10","key":"B2","article-title":"Statins and cardiomyocyte metabolism, friend or foe?","volume":"10","author":"Somers","year":"2023","journal-title":"J Cardiovasc Dev Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2016.09.001"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059344"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/phar.1194"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-024-01246-y"},{"issue":"6","key":"B7","first-page":"631","article-title":"Statin therapy: review of safety and potential side effects","volume":"32","author":"Ramkumar","year":"2016","journal-title":"Acta Cardiol Sin"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.121"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3138\/ptc.2012-65"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2022.11.010"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.02.049"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0216421"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2022.174906"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14136"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.08.002"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.312782"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01003.2020"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2019.03.012"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02150-w"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.67.040403.114521"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-010-0794-4"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200503000-00007"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/531465"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-2-25"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz105"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1080\/17410541.2024.2342223"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-3-22"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2122140119"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15893"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nature13950"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature14063"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nature13916"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.075"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2400497121"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2022.04.010"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(03)74976-5"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.71.3.788"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(76)90130-6"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1021\/jm00155a040"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1345\/aph.10366"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.2522\/ptj.20080155"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1172\/JCI162891"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2019.11.019"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.761636"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31887"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000004786"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.2217\/pgs-2018-0106"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa278"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0172551"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo1272"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2005.03.010"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4169"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3235"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nature09471"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/194490\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:06:20Z","timestamp":1779210380000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/194490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":56,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,10,23]]},"published-print":{"date-parts":[[2025,12,15]]}},"alternative-id":["10.1172\/JCI194490"],"URL":"https:\/\/doi.org\/10.1172\/jci194490","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"article-number":"e194490"}}