{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:28:44Z","timestamp":1791685724678,"version":"4.3.4"},"reference-count":65,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,5,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Exercise training, and catecholaminergic stimulation, increase the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy correlated with plakophilin-2 (PKP2) mutations. Separate data show that reduced abundance of PKP2 leads to dysregulation of intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      ) homeostasis. Here, we study the relation between excercise, catecholaminergic stimulation, Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      homeostasis, and arrhythmogenesis in PKP2-deficient murine hearts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Experiments were performed in myocytes from a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout murine line (PKP2cKO). For training, mice underwent 75 minutes of treadmill running once per day, 5 days each week for 6 weeks. We used multiple approaches including imaging, high-resolution mass spectrometry, electrocardiography, and pharmacological challenges to study the functional properties of cells\/hearts in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      In myocytes from PKP2cKO animals, training increased sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      load, increased the frequency and amplitude of spontaneous ryanodine receptor (ryanodine receptor 2)\u2013mediated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release events (sparks), and changed the time course of sarcomeric shortening. Phosphoproteomics analysis revealed that training led to hyperphosphorylation of phospholamban in residues 16 and 17, suggesting a catecholaminergic component. Isoproterenol-induced increase in Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      transient amplitude showed a differential response to \u03b2-adrenergic blockade that depended on the purported ability of the blockers to reach intracellular receptors. Additional experiments showed significant reduction of isoproterenol-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      sparks and ventricular arrhythmias in PKP2cKO hearts exposed to an experimental blocker of ryanodine receptor 2 channels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Exercise disproportionately affects Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      homeostasis in PKP2-deficient hearts in a manner facilitated by stimulation of intracellular \u03b2-adrenergic receptors and hyperphosphorylation of phospholamban. These cellular changes create a proarrhythmogenic state that can be mitigated by ryanodine receptor 2 blockade. Our data unveil an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of PKP2 deficit. We suggest that membrane-permeable \u03b2-blockers are potentially more efficient for patients with arrhythmogenic right ventricular cardiomyopathy, highlight the potential for ryanodine receptor 2 channel blockers as treatment for the control of heart rhythm in the population at risk, and propose that PKP2-dependent and phospholamban-dependent arrhythmogenic right ventricular cardiomyopathy\u2013related arrhythmias have a common mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.121.057757","type":"journal-article","created":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T05:00:20Z","timestamp":1651381220000},"page":"1480-1496","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":62,"title":["Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2\u2013Deficient Hearts"],"prefix":"10.1161","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1656-4447","authenticated-orcid":true,"given":"Chantal J.M.","family":"van Opbergen","sequence":"first","affiliation":[{"name":"The Leon Charney Division of Cardiology, New York University Grossmann School of Medicine (C.J.M.v.O., J.-C.K., M.C., M.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3958-6382","authenticated-orcid":true,"given":"Navratan","family":"Bagwan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (N.B., S.R.M., A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4700-2711","authenticated-orcid":true,"given":"Svetlana R.","family":"Maurya","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (N.B., S.R.M., A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon-Chul","family":"Kim","sequence":"additional","affiliation":[{"name":"The Leon Charney Division of Cardiology, New York University Grossmann School of Medicine (C.J.M.v.O., J.-C.K., M.C., M.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0921-1835","authenticated-orcid":true,"given":"Abigail N.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN (A.N.S., J.N.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-1792","authenticated-orcid":true,"given":"Daniel J.","family":"Blackwell","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (D.J.B., B.C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0885-636X","authenticated-orcid":true,"given":"Jeffrey N.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN (A.N.S., J.N.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4956-9735","authenticated-orcid":true,"given":"Bj\u00f6rn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (D.J.B., B.C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Cerrone,","sequence":"additional","affiliation":[{"name":"The Leon Charney Division of Cardiology, New York University Grossmann School of Medicine (C.J.M.v.O., J.-C.K., M.C., M.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Lundby","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (N.B., S.R.M., A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2085-5589","authenticated-orcid":true,"given":"Mario","family":"Delmar","sequence":"additional","affiliation":[{"name":"The Leon Charney Division of Cardiology, New York University Grossmann School of Medicine (C.J.M.v.O., J.-C.K., M.C., M.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2014.02.008"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0200-7"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1701400"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1509267"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.114.001003"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu509"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.06.033"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.114.001471"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euaa105"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2018.09.010"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.043504"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euy007"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.113.001224"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2019.01.019"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00127-0"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.039710"},{"key":"e_1_3_3_18_2","first-page":"ehab772","article-title":"Role of PKP2 expression on the exercise-mediated differential transcriptome of adult cardiac ventricular myocytes.","volume":"19","author":"Cerrone M","year":"2021","unstructured":"Cerrone, M, Marron-Linares, GM, van Opbergen, CJM, Costa, S, Bourfiss, M, Perez-Hernandez, M, Schlamp, F, Sanchis, F, Malkani, K, Drenkova, K, et al. 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