Binding of LncRNA-DACH1 to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility

Abstract Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. The study aims to explore whether lncRNA-DACH1(lncDACH1) can regulate the distribution of Nav1.5 by binding to dystrophin and participate in ventricular arrhythmogenesis. LncDACH1 was confirmed to bind to dystrophin. Cardiomyocyte-specific transgenic overexpression of lncDACH1(lncDACH1-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. The opposite data were collected from lncDACH1 cardiomyocyte conditional knockout (lncDACH1-CKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in lncDACH1-TG mice in vivo and ex vivo. The conservative fragment of lncDACH1 inhibited membrane distribution of dystrophin and Nav1.5 and promoted the inducibility of ventricular arrhythmia. Upregulation of dystrophin in lncDACH1-TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5. The human homologue of lncDACH1 inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. Collectively, lncDACH1 regulates Nav1.5 membrane distribution by binding to dystrophin and participates in ventricular arrhythmogenesis.