Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts

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  • Chantal J.M. Van Opbergen
  • Navratan Bagwan
  • Svetlana R. Maurya
  • Joon Chul Kim
  • Abigail N. Smith
  • Daniel J. Blackwell
  • Jeffrey N. Johnston
  • Björn C. Knollmann
  • Marina Cerrone,
  • Lundby, Alicia
  • Mario Delmar

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 Ca2+(Ca2+i) homeostasis. Here, we study the relation between excercise, catecholaminergic stimulation, Ca2+ihomeostasis, 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 Ca2+load, increased the frequency and amplitude of spontaneous ryanodine receptor (ryanodine receptor 2)-mediated Ca2+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 Ca2+itransient 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 Ca2+isparks and ventricular arrhythmias in PKP2cKO hearts exposed to an experimental blocker of ryanodine receptor 2 channels. Conclusions: Exercise disproportionately affects Ca2+ihomeostasis 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.

Original languageEnglish
Issue number19
Pages (from-to)1480-1496
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.

    Research areas

  • arrhythmogenic right ventricular cardiomyopathy, exercise, phospholamban, plakophilins, receptors, adrenergic, beta-1

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