NEXN deficiency leads to dilated cardiomyopathy in human pluripotent stem cell-derived cardiomyocytes

Dilated cardiomyopathy (DCM) constitutes a major cause of heart failure, characterized by high mortality rates and a limited availability of effective therapeutic options. A substantial body of evidence indicates that mutations in the Nexilin (NEXN) gene are significant pathogenic contributors to DCM, and we have developed a NEXN-deficient human cardiac myocyte model that faithfully replicated the pathophysiological characteristics of DCM. This model addressed the limitations associated with interspecies physiological differences and was highly suitable for further investigation into the underlying pathogenesis. We demonstrated that NEXN was one of the important components in maintaining the structure and function of cardiomyocyte JMCs, and played a key regulatory role in maintaining the normal excitation-contraction coupling of cardiomyocytes. Meanwhile, NEXN also played a critical role in maintaining the normal energy metabolism of cardiomyocytes, and the loss of its function would lead to DCM. Furthermore, Levo-carnitine and SERCA2a Activator 1 were identified as promising therapeutic agents for the treatment of DCM. Our finding reveals a critical regulatory role of NEXN in JMCs and mitochondria to prevent the development of DCM. To investigate the function of NEXN in the pathogenesis of myocardial remodeling, we established a NEXN-deficient human cardiac myocyte (CM) model. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different cells at one time point. Comparative gene exprission profiling analysis of RNA-seq data for cells.

扩张型心肌病（Dilated cardiomyopathy, DCM）是心力衰竭的主要致病原因，以高死亡率与有效治疗手段匮乏为典型特征。大量研究证据表明，纽蛋白（Nexilin, NEXN）基因的突变是引发DCM的重要致病因素。我们成功构建了纽蛋白缺陷型人心肌细胞模型，该模型可忠实复现DCM的病理生理特征，解决了物种间生理差异带来的研究局限，十分适用于DCM潜在发病机制的深入探究。研究证实，纽蛋白是维持心肌细胞连接膜复合体（Junctional Membrane Complexes, JMCs）结构与功能的关键组分之一，在维持心肌细胞正常兴奋-收缩耦联过程中发挥核心调控作用。同时，纽蛋白对于维持心肌细胞正常能量代谢亦具有重要意义，其功能缺失可诱发DCM。此外，我们还筛选出左卡尼汀（Levo-carnitine）与肌浆网钙ATP酶2a激活剂1（SERCA2a Activator 1）两类极具开发前景的DCM治疗候选药物。本研究揭示了纽蛋白通过调控连接膜复合体与线粒体，进而阻断DCM发生发展的关键作用机制。为探究纽蛋白在心肌重构发病过程中的功能，我们构建了纽蛋白缺陷型人心肌细胞（Cardiac Myocyte, CM）模型。随后基于3株不同细胞在同一时间点的RNA测序（RNA-seq）数据开展基因表达谱分析，并对细胞的RNA测序数据进行了对比基因表达谱分析。