Isoform changes of action potential regulators in the ventricles of arrhythmogenic phospholamban-R14del humanized mouse hearts

Nov 14, 2022Metabolism: clinical and experimental

Changes in Heartbeat Control Proteins in the Lower Heart Chambers of Mice with a Human Heart Rhythm Mutation

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Abstract

More than 200 significant alternative splicing events were identified in the PLN-R14del mouse model compared to wild-type hearts.

Distinct alternative splicing profiles were observed in the right and left ventricles of PLN-R14del compared to wild-type mouse hearts.
The most affected biological process related to the splicing events is associated with cardiac cell action potential, especially in the right ventricle.
Alterations in splicing of the genes Trpm4 and Camk2d, which are involved in calcium regulation in the heart, were identified in PLN-R14del models.
Tissue-specific splicing factors Srrm4 and Nova1 may play a role as upstream regulators of the splicing changes observed in PLN-R14del cardiomyocytes.
Aberrant splicing in PLN-R14del may contribute to the increased risk of arrhythmias associated with arrhythmogenic cardiomyopathy.

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Arrhythmogenic cardiomyopathy (ACM) is characterized by life-threatening ventricular arrhythmias and sudden cardiac death and affects hundreds of thousands of patients worldwide. The deletion of Arginine 14 (p.R14del) in the phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is a key regulator of sarcoplasmic reticulum (SR) Cacycling and cardiac contractility. Despite global gene and protein expression studies, the molecular mechanisms of PLN-R14del ACM pathogenesis remain unclear. Using a humanized PLN-R14del mouse model and human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), we investigated the transcriptome-wide mRNA splicing changes associated with the R14del mutation. We identified >200 significant alternative splicing (AS) events and distinct AS profiles were observed in the right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts. Enrichment analysis of the AS events showed that the most affected biological process was associated with "cardiac cell action potential", specifically in the RV. We found that splicing of 2 key genes, Trpm4 and Camk2d, which encode proteins regulating calcium homeostasis in the heart, were altered in PLN-R14del mouse hearts and human iPSC-CMs. Bioinformatical analysis pointed to the tissue-specific splicing factors Srrm4 and Nova1 as likely upstream regulators of the observed splicing changes in the PLN-R14del cardiomyocytes. Our findings suggest that aberrant splicing may affect Ca-homeostasis in the heart, contributing to the increased risk of arrythmogenesis in PLN-R14del ACM. 2+ 2+

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Isoform changes of action potential regulators in the ventricles of arrhythmogenic phospholamban-R14del humanized mouse hearts

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