{"doi":"10.1161/circulationaha.121.057757","title":"Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2–Deficient Hearts","abstract":"Background: 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 2+ (Ca 2+ i ) homeostasis. Here, we study the relation between excercise, catecholaminergic stimulation, Ca 2+ i homeostasis, and arrhythmogenesis in PKP2-deficient murine hearts. Methods: 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. Results: In myocytes from PKP2cKO animals, training increased sarcoplasmic reticulum Ca 2+ load, increased the frequency and amplitude of spontaneous ryanodine receptor (ryanodine receptor 2)–mediated Ca 2+ 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 2+ i transient amplitude showed a differential response to β-adrenergic blockade that depended on the purported ability of the blockers to reach intracellular receptors. Additional experiments showed significant reduction of isoproterenol-induced Ca 2+ i sparks and ventricular arrhythmias in PKP2cKO hearts exposed to an experimental blocker of ryanodine receptor 2 channels. Conclusions: Exercise disproportionately affects Ca 2+ i homeostasis in PKP2-deficient hearts in a manner facilitated by stimulation of intracellular β-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 β-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–related arrhythmias have a common mechanism.","journal":"Circulation","year":2022,"id":237211,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":62,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":859052,"name":"Navratan Bagwan","orcid":"0000-0002-3958-6382","position":1,"is_corresponding":false},{"id":855148,"name":"Svetlana Maurya","orcid":"0000-0002-4700-2711","position":2,"is_corresponding":false},{"id":859768,"name":"Joon-Chul Kim","orcid":null,"position":3,"is_corresponding":false},{"id":859053,"name":"Abigail N. Smith","orcid":"0000-0003-0921-1835","position":4,"is_corresponding":false},{"id":314113,"name":"Daniel J. Blackwell","orcid":"0000-0001-6619-1792","position":5,"is_corresponding":false},{"id":859054,"name":"Jeffrey N. Johnston","orcid":"0000-0002-0885-636X","position":6,"is_corresponding":false},{"id":236808,"name":"Björn C. Knollmann","orcid":"0000-0003-4956-9735","position":7,"is_corresponding":false},{"id":859769,"name":"Marina Cerrone,","orcid":null,"position":8,"is_corresponding":false},{"id":55701,"name":"Alicia Lundby","orcid":"0000-0002-1612-6041","position":9,"is_corresponding":false},{"id":350416,"name":"Mario Delmar","orcid":"0000-0002-2085-5589","position":10,"is_corresponding":false},{"id":681660,"name":"Chantal J.M. van Opbergen","orcid":"0000-0002-1656-4447","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:22:08.925400Z","pmid":"35491884","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}