Mettl3 deficiency leads to the upregulation of Cav1.2 and increases arrhythmia susceptibility in mice: Mettl3 regulates L-type Ca currents of cardiomyocytes

Methyltransferase-like 3 (Mettl3) is a component of methyltransferase complex that mediates m (6)A modification of RNAs, and participates in multiple biological processes. However, the role of Mettl3 in cardiac electrophysiology remains unknown. This study aims to explore the ventricular arrhythmia susceptibility of Mettl3 (+/–) mice and the underlying mechanisms. Mice were anesthetized with 2% avertin (0.1 mL/10 g body weight) for echocardiography and programmed electrical pacing. Whole-cell patch clamp technique was used to examine the electrophysiological property of cardiomyocytes. The expression of Cav1.2 was determined by qRT-PCR and western blot analysis. The m (6)A medication of mRNA was examined by MeRIP-Seq and MeRIP-qPCR. No differences are found in the morphology and function of the hearts between Mettl3 (+/–) mice and wild-type (WT) controls. The QT and QTc intervals of Mettl3 (+/–) mice are significantly longer. High-frequency electrical stimulation showed that heterozygous knockout of Mettl3 increases ventricular arrhythmia susceptibility. The whole-cell patch-clamp recordings showed that the APD is prolonged in Mettl3 (+/–) ventricular myocytes and more EADs were observed. The density of I (Ca-L) is substantially increased in ventricular myocytes of Mettl3 (+/–) mice. The pore-forming subunit of L-type calcium channel Cav1.2 is upregulated in Mettl3 (+/–) mice, while the mRNA of its coding gene CACNA1C does not change. MeRIP-Seq and MeRIP-qPCR showed that the m (6)A methylation of CACNA1C mRNA is decreased in cultured Mettl3-knockdown cardiomyocytes and Mettl3 (+/–) hearts. Collectively, deficiency of Mettl3 increases ventricular arrhythmia susceptibility due to the upregulation of Cav1.2 by reducing m (6)A modification on CACNA1CmRNA in mice. This study highlights the role of m (6)A modification in the regulation of cardiac electrophysiology.