Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts
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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.
|Status||Udgivet - 2022|
This work was supported by National Institutes of Health (NIH) grants RO1-HL134328, RO1-HL136179, and RO1-HL145911 (to Dr Delmar ), a Transatlantic Network of Excellence from the Leducq Foundation (to Drs Delmar and Lundby), a Transformational Project award from the American Heart Association 18TPA34230006 (to Dr Cerrone), the Wilton W. Webster Fellowship in Pediatric Electrophysiology from Heart Rhythm Society, and an American Heart Association Postdoctoral Fellowship (to Dr van Opbergen). The mass spectrometry measurements were performed at The Novo Nordisk Foundation Center for Protein Research, which is funded in part by a generous donation from the Novo Nordisk Foundation (NNF14CC0001). The project was supported by The Danish Council for independent Research (DFF–0134-00054B) and the Novo Nordisk Foundation (NNF18OC0052844) to Dr Lundby. The Vanderbilt group was supported in part by NIH grants National Heart, Lung, and Blood Institute (NHLBI) R35 HL144980 (to Dr Knollmann), NHLBI R01 HL151223 (to Drs Johnston and Knollmann), NHLBI F32 HL140874 (to Dr Blackwell), NHLBI F31 HL151125 (to Dr Smith), the Leducq Foundation grant 18CVD05 (to Dr Knollmann), the American Heart Association grant 19SFRN34830019 (to Dr Knollmann), PhRMA Foundation Postdoctoral Award (to Dr Blackwell).
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