Binding of LncDACH1 to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility

• DOI: 10.7554/elife.89690.4
• Publication Date: 2025-01-07T13:15:42Z
• Authors: Genlong Xue; Jiming Yang; Yang Zhang; Ying Yang; Ruixin Zhang; Desheng Li; Tao Tian; Jialiang Li; Xiaofang Zhang; Changzhu Li; Xingda Li; Jiqin Yang; Kewei Shen; Yang Guo; Xuening Liu; Guohui Yang; Lina Xuan; Hongli Shan; Yanjie Lu; Yang Baofeng; Zhenwei Pan
• Keywords: Nav1.5

Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved the regulation cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed lncRNA- Dachshund homolog 1 ( lncDach1 ) can bind to dystrophin, which drove us investigate if regulate by interfering with dystrophin. Western blot and immunofluorescent staining cardiomyocyte-specific transgenic overexpression -TG) reduced distribution dystrophin Meanwhile, peak I Na was hearts -TG mice than wild-type (WT) controls. The opposite western blot, patch clamp were collected from cardiomyocyte conditional knockout -cKO) mice. Moreover, increased ventricular arrhythmia susceptibility observed vivo ex vivo. conservative fragment inhibited Nav1.5, promoted inducibility arrhythmia. Strikingly, activation transcription dCas9-SAM system rescued impaired prevented occurrence Furthermore, transaortic constriction (TAC) induced failing hearts, And expression regulated hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), binds decreases stability. human homologue lncDACH1 iPS-differentiated findings provide novel insights into mechanism targeting development arrhythmias.