{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T08:46:20Z","timestamp":1791708380661,"version":"4.3.4"},"reference-count":32,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R15HL154073A1"],"award-info":[{"award-number":["R15HL154073A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL166169\u201001A1"],"award-info":[{"award-number":["R01HL166169\u201001A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the sarcoplasmic reticulum (SR) calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) release channel RyR2 or its accessory proteins, including calsequestrin\u20102 (CASQ2). RyR2 dysfunction or leak is the hallmark feature of CPVT and directly triggers arrhythmias. Despite this electrical instability, CPVT hearts are typically anatomically normal and lack pathological remodelling. Therefore, we hypothesized that introducing additional stressors, such as metabolic stress, would worsen cardiac arrhythmias and potentially trigger pathological remodelling. To test this hypothesis, metabolic stress was introduced by crossbreeding a CPVT model of CASQ2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice with the Akita mouse, a genetic model of diabetes that also lacks cardiac remodelling. We found that dysregulation of myocyte Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling was exacerbated in Akita\u2010CASQ2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells, which exhibited slower Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient decay kinetics and increased arrhythmogenic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    waves. Akita\u2010CASQ2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice also displayed more severe arrhythmias, diastolic dysfunction, and cardiac hypertrophy, but without evidence of fibrosis, cell death, or worsened metabolic dysfunction. Finally, mitochondrial reactive oxygen species production was increased in Akita\u2010CASQ2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cardiomyocytes, which may contribute to the more severe pathological phenotype. Overall, our results suggest that metabolic stress can aggravate dysregulated myocyte Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling and promote cardiac dysfunction in CPVT hearts.\n                  <\/jats:p>","DOI":"10.1113\/ep094053","type":"journal-article","created":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T07:49:53Z","timestamp":1791704993000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic stress exacerbates Ca\n                    <sup>2+<\/sup>\n                    dysregulation and arrhythmias in catecholaminergic polymorphic ventricular tachycardia"],"prefix":"10.1113","author":[{"given":"Valeria","family":"Gomez","sequence":"first","affiliation":[{"name":"Food Science and Human Nutrition Department University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6685-0358","authenticated-orcid":false,"given":"Arpita","family":"Deb","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Mississippi State University  Starkville Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoxin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Cheng","sequence":"additional","affiliation":[{"name":"Food Science and Human Nutrition Department University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin K.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Food Science and Human Nutrition Department University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinying","family":"Yang","sequence":"additional","affiliation":[{"name":"Food Science and Human Nutrition Department University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongmin","family":"Lee","sequence":"additional","affiliation":[{"name":"Food Science and Human Nutrition Department University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjorn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University School of Medicine  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Food Science and Human Nutrition Department University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4797-8105","authenticated-orcid":false,"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Food Science and Human Nutrition Department University of Florida  Gainesville Florida USA"},{"name":"Department of Biological Sciences Mississippi State University  Starkville Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,11]]},"reference":[{"issue":"6","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"H2096","DOI":"10.1152\/ajpheart.00452.2009","article-title":"Type 1 diabetic cardiomyopathy in the Akita (Ins2WT\/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function","volume":"297","author":"Basu R.","year":"2009","journal-title":"American Journal of Physiology\u2010Heart and Circulatory Physiology"},{"issue":"2","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1093\/cvr\/cvt024","article-title":"\u2018Ryanopathy\u2019: Causes and manifestations of RyR2 dysfunction in heart failure","volume":"98","author":"Belevych A. E.","year":"2013","journal-title":"Cardiovascular Research"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","DOI":"10.1007\/978-94-010-0658-3","volume-title":"Excitation\u2010contraction coupling and cardiac contractile force","author":"Bers D. M.","year":"2001"},{"issue":"11","key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.2337\/db08-0079","article-title":"Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3","volume":"57","author":"Bugger H.","year":"2008","journal-title":"Diabetes"},{"issue":"1","key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1111\/j.1440-1681.2006.04331.x","article-title":"Gender disparity of streptozotocin\u2010induced intrinsic contractile dysfunction in murine ventricular myocytes: Role of chronic activation of Akt","volume":"33","author":"Ceylan\u2010Isik A. F.","year":"2006","journal-title":"Clinical and Experimental Pharmacology & Physiology"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ceca.2025.103106","article-title":"Ablation of mitochondrial calcium uniporter alleviates cardiac dysfunction in type 1 diabetes","volume":"133","author":"Deb A.","year":"2026","journal-title":"Cell Calcium"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jmccpl.2024.100093","article-title":"Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT","volume":"10","author":"Deb A.","year":"2024","journal-title":"Journal of Molecular and Cellular Cardiology Plus"},{"issue":"2","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.3390\/cells12020204","article-title":"Genetic inhibition of mitochondrial permeability transition pore exacerbates ryanodine receptor 2 dysfunction in arrhythmic disease","volume":"12","author":"Deb A.","year":"2023","journal-title":"Cells"},{"issue":"1","key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.hrthm.2008.09.013","article-title":"Molecular basis of catecholaminergic polymorphic ventricular tachycardia","volume":"6","author":"Gy\u00f6rke S.","year":"2009","journal-title":"Heart Rhythm"},{"issue":"9","key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1085\/jgp.201711808","article-title":"The role of luminal Ca regulation in Ca signaling refractoriness and cardiac arrhythmogenesis","volume":"149","author":"Gy\u00f6rke S.","year":"2017","journal-title":"Journal of General Physiology"},{"issue":"2","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/cvr\/cvm038","article-title":"Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease","volume":"77","author":"Gyorke S.","year":"2008","journal-title":"Cardiovascular Research"},{"issue":"4","key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s00395-020-0797-z","article-title":"Increased RyR2 activity is exacerbated by calcium leak\u2010induced mitochondrial ROS","volume":"115","author":"Hamilton S.","year":"2020","journal-title":"Basic Research in Cardiology"},{"issue":"1","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/cvr\/cvt233","article-title":"Ryanodine receptor phosphorylation by oxidized CaMKII contributes to the cardiotoxic effects of cardiac glycosides","volume":"101","author":"Ho H.\u2010T.","year":"2014","journal-title":"Cardiovascular Research"},{"issue":"7","key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1161\/CIRCRESAHA.114.303391","article-title":"Divergent regulation of ryanodine receptor 2 calcium release channels by arrhythmogenic human calmodulin missense mutants","volume":"114","author":"Hwang H. S.","year":"2014","journal-title":"Circulation Research"},{"issue":"2","key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1093\/cvr\/cvs334","article-title":"Up\u2010regulation of sarcoplasmic reticulum Ca(2+) uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2","volume":"98","author":"Kalyanasundaram A.","year":"2013","journal-title":"Cardiovascular Research"},{"issue":"9","key":"e_1_2_9_17_1","first-page":"2510","article-title":"Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia","volume":"116","author":"Knollmann B. C.","year":"2006","journal-title":"Journal of Clinical Investigation"},{"issue":"24","key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"9232","DOI":"10.1073\/pnas.0602956103","article-title":"Estrogens protect pancreatic beta\u2010cells from apoptosis and prevent insulin\u2010deficient diabetes mellitus in mice","volume":"103","author":"Le May C.","year":"2006","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"2","key":"e_1_2_9_19_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1093\/cvr\/cvv222","article-title":"Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT","volume":"108","author":"Liu B.","year":"2015","journal-title":"Cardiovascular Research"},{"issue":"9","key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1113\/jphysiol.2013.264689","article-title":"Genetic ablation of ryanodine receptor 2 phosphorylation at Ser\u20102808 aggravates Ca(2+)\u2010dependent cardiomyopathy by exacerbating diastolic Ca2+ release","volume":"592","author":"Liu B.","year":"2014","journal-title":"The Journal of Physiology"},{"issue":"10","key":"e_1_2_9_21_1","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1161\/CIRCRESAHA.121.318241","article-title":"Cardiac energy metabolism in heart failure","volume":"128","author":"Lopaschuk G. D.","year":"2021","journal-title":"Circulation Research"},{"issue":"8","key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1113\/jphysiol.2014.286518","article-title":"Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin\u2010induced cardiac and skeletal muscle myopathy","volume":"593","author":"Min K.","year":"2015","journal-title":"The Journal of Physiology"},{"issue":"13","key":"e_1_2_9_23_1","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1093\/eurheartj\/ehad028","article-title":"Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH\u2010driven mitochondrial respiration","volume":"44","author":"Nollet E. E.","year":"2023","journal-title":"European Heart Journal"},{"issue":"12","key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"H1807","DOI":"10.1152\/ajpheart.00979.2012","article-title":"Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes: Effect of pravastatin","volume":"305","author":"Rajab M.","year":"2013","journal-title":"American Journal of Physiology\u2010Heart and Circulatory Physiology"},{"issue":"4","key":"e_1_2_9_25_1","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1152\/japplphysiol.91280.2008","article-title":"Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation","volume":"106","author":"Shao C. H.","year":"2009","journal-title":"The Journal of Applied Physiology (1985)"},{"key":"e_1_2_9_26_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.redox.2023.102727","article-title":"FoxO1 regulates adipose transdifferentiation and iron influx by mediating Tgfbeta1 signaling pathway","volume":"63","author":"Shi L.","year":"2023","journal-title":"Redox Biology"},{"issue":"6","key":"e_1_2_9_27_1","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1042\/CS20230973","article-title":"Loss of FoxO1 activates an alternate mechanism of mitochondrial quality control for healthy adipose browning","volume":"138","author":"Shi L.","year":"2024","journal-title":"Clinical Science"},{"issue":"13","key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1093\/cvr\/cvab324","article-title":"SR\u2010mitochondria crosstalk shapes Ca signalling to impact pathophenotype in disease models marked by dysregulated intracellular Ca release","volume":"118","author":"Tow B. D.","year":"2022","journal-title":"Cardiovascular Research"},{"issue":"8","key":"e_1_2_9_29_1","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1161\/CIRCRESAHA.109.209312","article-title":"Catecholaminergic polymorphic ventricular tachycardia is caused by mutation\u2010linked defective conformational regulation of the ryanodine receptor","volume":"106","author":"Uchinoumi H.","year":"2010","journal-title":"Circulation Research"},{"issue":"8","key":"e_1_2_9_30_1","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1113\/jphysiol.2014.286153","article-title":"Rapid changes in NADH and flavin autofluorescence in rat cardiac trabeculae reveal large mitochondrial complex II reserve capacity","volume":"593","author":"W\u00fcst R. C. I.","year":"2015","journal-title":"The Journal of Physiology"},{"issue":"6","key":"e_1_2_9_31_1","article-title":"Estrogen protects cardiac function and energy metabolism in dilated cardiomyopathy induced by loss of cardiac IRS1 and IRS2","volume":"15","author":"Yan H.","year":"2022","journal-title":"Circulation: Heart Failure"},{"issue":"11","key":"e_1_2_9_32_1","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.2337\/diabetes.54.11.3082","article-title":"Effects of diabetes on ryanodine receptor Ca release channel (RyR2) and Ca2+ homeostasis in rat heart","volume":"54","author":"Yaras N.","year":"2005","journal-title":"Diabetes"},{"issue":"5","key":"e_1_2_9_33_1","doi-asserted-by":"crossref","first-page":"887","DOI":"10.2337\/diab.46.5.887","article-title":"A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early\u2010onset NIDDM in nonobese C57BL\/6 (Akita) mutant mice","volume":"46","author":"Yoshioka M.","year":"1997","journal-title":"Diabetes"}],"container-title":["Experimental Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP094053","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/EP094053","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP094053","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T07:49:58Z","timestamp":1791704998000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/EP094053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,11]]},"references-count":32,"alternative-id":["10.1113\/EP094053"],"URL":"https:\/\/doi.org\/10.1113\/ep094053","archive":["Portico"],"relation":{},"ISSN":["0958-0670","1469-445X"],"issn-type":[{"value":"0958-0670","type":"print"},{"value":"1469-445X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,11]]},"assertion":[{"value":"2026-05-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"EP094053"}}