{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:46:02Z","timestamp":1768517162915,"version":"3.49.0"},"posted":{"date-parts":[[2024,12,9]]},"group-title":"Physiology","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Stromal interaction molecule 1 (STIM1) is a key regulator of intracellular calcium (Ca\u00b2\u207a) homeostasis and mitochondrial function, two tightly coupled processes that critically determine electro-mechanical function and post-myocardial infarction (MI) remodeling.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Hypothesis<\/jats:title>\n                  <jats:p>We hypothesized that cardiomyocyte STIM1 deficiency induced by AAV9-mediated knockdown triggers mitochondrial and metabolic remodeling that alters the electrophysiological (EP) substrate and exacerbates post-MI heart failure.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Eight-week-old mice received cardiotropic AAV9-mediated delivery of short hairpin RNA targeting STIM1 (AAV9-shSTIM1) or a control construct (AAV9-shLuc\/PBS). Four weeks later,\n                    <jats:italic>in vivo<\/jats:italic>\n                    echocardiography followed by\n                    <jats:italic>ex vivo<\/jats:italic>\n                    optical action potential (AP) mapping were performed to determine the impact of myocardial STIM1 downregulation on mechanical and EP properties. Electron microscopy and western blotting were performed to assess mitochondrial network architecture, dynamics and related metabolic signaling. A separate cohort of mice underwent a 30-minute coronary occlusion followed by reperfusion to induce MI. One week post-MI, left ventricular (LV) function, structural remodeling, and EP properties were assessed in mice with and without myocardial STIM1 knockdown.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    AAV9-shSTIM1 delivery markedly reduced cardiomyocyte STIM1 expression. STIM1 downregulation induced extensive mitochondrial fragmentation, increased DRP1 phosphorylation at S616 (+55%,\n                    <jats:italic>p<\/jats:italic>\n                    =0.0057), reduced OPA1 expression, and altered AMPK-dependent signaling (reduced phospho-ACC and phospho-Raptor). These mitochondrial and metabolic abnormalities were accompanied by EP instability. In response to\n                    <jats:italic>in vivo<\/jats:italic>\n                    I\/R injury, shSTIM1 mice exhibited significantly greater LV dysfunction (\u221244.3% vs. \u221212.2% fractional shortening,\n                    <jats:italic>p<\/jats:italic>\n                    &lt;0.0001) and more pronounced structural and EP remodeling with formation of spatially discordant AP alternans 1-week following MI indicative of accelerated heart failure progression.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>AAV9-mediated STIM1 knockdown exacerbates post-MI cardiac dysfunction likely through impaired mitochondrial dynamics and disrupted metabolic signaling. Beyond worsening post-MI function, STIM1 deficiency alone induces profound EP remodeling, underscoring the pivotal role of cardiomyocyte STIM1 in coordinating mitochondrial homeostasis, electrical stability, and cardiac recovery after injury.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.12.05.625436","type":"posted-content","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T18:00:11Z","timestamp":1733767211000},"source":"Crossref","is-referenced-by-count":0,"title":["Myocardial STIM1 deficiency triggers mitochondrial fission to impair electrophysiological function and exacerbate post-MI remodeling"],"prefix":"10.64898","author":[{"given":"Marine","family":"Cacheux","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Velasco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan M.","family":"Granger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Strauss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9146-8407","authenticated-orcid":false,"given":"Fadi G.","family":"Akar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025110223551786000_2024.12.05.625436v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2018.11.008"},{"key":"2025110223551786000_2024.12.05.625436v2.2","first-page":"e2318874121","article-title":"Essential role of N-terminal SAM regions in STIM1 multimerization and function","volume":"121","year":"21 2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025110223551786000_2024.12.05.625436v2.3","first-page":"2496","article-title":"SOCE Is Important for Maintaining Sarcoplasmic Calcium Content and Release in Skeletal Muscle Fibers","volume":"113","year":"5 2017","journal-title":"Biophys J"},{"key":"2025110223551786000_2024.12.05.625436v2.4","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.116.307869"},{"key":"2025110223551786000_2024.12.05.625436v2.5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022724-105330"},{"key":"2025110223551786000_2024.12.05.625436v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.01.020"},{"key":"2025110223551786000_2024.12.05.625436v2.7","first-page":"125","article-title":"Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction","volume":"121","year":"7 2017","journal-title":"Circ Res"},{"key":"2025110223551786000_2024.12.05.625436v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.11.003"},{"key":"2025110223551786000_2024.12.05.625436v2.9","first-page":"172","article-title":"Essential role of STIM1 in the development of cardiomyocyte hypertrophy","volume":"389","year":"6 2009","journal-title":"Biochem Biophys Res Commun"},{"key":"2025110223551786000_2024.12.05.625436v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.07.032"},{"key":"2025110223551786000_2024.12.05.625436v2.11","first-page":"1458","article-title":"Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2\/Akt Signaling","volume":"133","year":"12 2016","journal-title":"Circulation"},{"key":"2025110223551786000_2024.12.05.625436v2.12","first-page":"E4792","article-title":"STIM1 enhances SR Ca2+ content through binding phospholamban in rat ventricular myocytes","volume":"112","year":"25 2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025110223551786000_2024.12.05.625436v2.13","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.119.007382"},{"key":"2025110223551786000_2024.12.05.625436v2.14","first-page":"H446","article-title":"STIM1\/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology","volume":"305","year":"15 2013","journal-title":"American journal of physiology Heart and circulatory physiology"},{"key":"2025110223551786000_2024.12.05.625436v2.15","first-page":"H1231","article-title":"Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function","volume":"306","year":"15 2014","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2025110223551786000_2024.12.05.625436v2.16","first-page":"H1014","article-title":"Novel role of the ER\/SR Ca(2+) sensor STIM1 in the regulation of cardiac metabolism","volume":"316","year":"1 2019","journal-title":"American journal of physiology Heart and circulatory physiology"},{"key":"2025110223551786000_2024.12.05.625436v2.17","doi-asserted-by":"crossref","unstructured":"Collins HE , Zhang D , Chatham JC . 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