{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T03:14:31Z","timestamp":1787973271749,"version":"build-2784847793"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Variants in\n                      <jats:italic toggle=\"yes\">PRKAG2<\/jats:italic>\n                      cause hypertrophic cardiomyopathy and conduction disturbances. Although prior studies associated\n                      <jats:italic toggle=\"yes\">PRKAG2<\/jats:italic>\n                      -related hypertrophy with increased glycogen storage, many hypertrophic cardiomyopathy phenotypes remain unexplained. We aimed to uncover how\n                      <jats:italic toggle=\"yes\">PRKAG2<\/jats:italic>\n                      variants induce myocyte hypertrophy and electrical changes during early cardiac development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We generated transgenic zebrafish expressing wild-type or pathogenic variant\n                      <jats:italic toggle=\"yes\">Prkag2<\/jats:italic>\n                      under a myocardium-specific promoter, Tg(\n                      <jats:italic toggle=\"yes\">cmcl2<\/jats:italic>\n                      :\n                      <jats:italic toggle=\"yes\">Prkag2<\/jats:italic>\n                      <jats:sup>WT<\/jats:sup>\n                      ) (Tg\n                      <jats:sup>WT<\/jats:sup>\n                      ) and Tg(\n                      <jats:italic toggle=\"yes\">cmcl2<\/jats:italic>\n                      :\n                      <jats:italic toggle=\"yes\">Prkag2<\/jats:italic>\n                      <jats:sup>R299Q<\/jats:sup>\n                      ) (Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      ), respectively, and examined cardiac electrophysiology, contractile function, and cytoarchitecture during cardiogenesis and in adult hearts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      fish showed hypertrophic cardiomyocytes and progressive contractile abnormalities, recapitulating human hypertrophic cardiomyopathy phenotypes. Cardiomyocyte glycogen was elevated in adult but not embryonic hearts. Despite the absence of glycogen accumulation at 6 days post-fertilization, Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transient durations, compared to Tg\n                      <jats:sup>WT<\/jats:sup>\n                      and wild-type (T\u00fcbingen\/AB [TuAB]). We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      . Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPK\u03b32 and myosin, enhanced by the R299Q variant and accompanied by increased AMPK\u03b32 localization to the myofilament. NCX (Na\n                      <jats:sup>+<\/jats:sup>\n                      \/Ca\n                      <jats:sup>2+<\/jats:sup>\n                      exchanger) inhibition increased Ca\n                      <jats:sup>2+<\/jats:sup>\n                      duration and diastolic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      in Tg\n                      <jats:sup>WT<\/jats:sup>\n                      but not Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      hearts, indicating reduced free cytosolic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      for NCX-mediated extrusion in Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      . These findings suggest that enhanced AMPK\u03b32-myosin interaction may promote myofilament Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      retention, thereby prolonging Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      transient duration and action potential duration in the mutant. Notably, the myosin inhibitor mavacamten reduced AMPK\u03b32-myosin interaction in Tg\n                      <jats:sup>R299Q<\/jats:sup>\n                      hearts, and both mavacamten and\n                      <jats:italic toggle=\"yes\">vmhcl<\/jats:italic>\n                      knockdown rescued the early electrophysiological abnormalities.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">PRKAG2<\/jats:italic>\n                      variant altered cardiac excitability, contractility, and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling during cardiogenesis, independent of glycogen accumulation. Enhanced interactions between AMPK\u03b32 and myosin contributed to these early changes. Our study revealed a novel link between cellular energy sensing and contractile machinery, with therapeutic potential for modulating contractile function in cardiomyopathies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.126.328910","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T09:00:48Z","timestamp":1783587648000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["AMPK\u03b32 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin"],"prefix":"10.1161","volume":"139","author":[{"given":"Qianyun","family":"Ge","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Therapeutics (Q.G., W.Z.), The Ohio State University, College of Medicine, Columbus."},{"name":"Dorothy M. Davis Heart and Lung Research Institute (Q.G., H.-L.H., J.M.H., K.C., S.M.H., W.Z.), The Ohio State University, College of Medicine, Columbus."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4281-6852","authenticated-orcid":true,"given":"Kusumika","family":"Saha","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (K.S., M.L.B., W.H.B., A.K.C., M.H., R.A.V., D.Q., A.W., E.P., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah L.","family":"Burch","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (K.S., M.L.B., W.H.B., A.K.C., M.H., R.A.V., D.Q., A.W., E.P., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willow H.","family":"Battista","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (K.S., M.L.B., W.H.B., A.K.C., M.H., R.A.V., D.Q., A.W., E.P., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashmita","family":"KC","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (K.S., M.L.B., W.H.B., A.K.C., M.H., R.A.V., D.Q., A.W., E.P., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7240-0028","authenticated-orcid":true,"given":"Max","family":"Homilius","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (K.S., M.L.B., W.H.B., A.K.C., M.H., R.A.V., D.Q., A.W., E.P., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-1376","authenticated-orcid":true,"given":"Rachelle A.","family":"Victorio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (K.S., M.L.B., W.H.B., A.K.C., M.H., R.A.V., D.Q., A.W., E.P., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4381-232X","authenticated-orcid":true,"given":"Dajun","family":"Quan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (K.S., M.L.B., W.H.B., A.K.C., M.H., R.A.V., D.Q., A.W., E.P., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5944-1252","authenticated-orcid":true,"given":"Hsiang-Ling","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology (H.-L.H., J.M.H., K.C., S.M.H.), The Ohio State University, College of Medicine, Columbus."},{"name":"Dorothy M. 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