The effect of utrophin on the electrophysiological properties of DMD hiPSC-derived cardiomyocytes

DMD is a genetic disease, which leads to muscle weakness and cardiomyopathy. The latter remains incurable, being the main cause of death in DMD, therefore new therapeutic strategies are being sought to provide effective treatment. One of them considers upregulation of utrophin, a protein structurally and functionally homologous to dystrophin. In this study proteomic analysis of dystrophin-deficient and both dystrophin- and utrophin-deficient hiPSC-CM indicated on considerable differences in terms of contraction-related mechanisms. We thus investigated the role of utrophin in the maintenance of electrophysiological properties of DMD hiPSC-CM using the cells with additional utrophin deficiency and with utrophin upregulation. Obtained results indicated on disturbance of calcium handling in DMD hiPSC-CM, even more pronounced in DMD/UTRN KO hiPSC-CM and increased values of AHP in DMD hiPSC-CM. Utrophin upregulation improved both calcium oscillations and AHP values. Our findings highlight utrophin as important in the maintenance of the electrophysiological properties of DMD hiPSC-CM.

杜氏肌营养不良症（Duchenne Muscular Dystrophy, DMD）是一种遗传性疾病，可引发肌肉无力与心肌病。其中心肌病迄今尚无治愈方案，亦是DMD患者的主要致死原因，因此学界正积极探索可实现有效治疗的新型治疗策略。其中一种策略着眼于上调肌调蛋白（utrophin）——一种在结构与功能上与抗肌萎缩蛋白（dystrophin）高度同源的蛋白质。本研究针对抗肌萎缩蛋白缺陷型、同时缺失抗肌萎缩蛋白与肌调蛋白的诱导多能干细胞源性心肌细胞（human induced pluripotent stem cell-derived cardiomyocytes, hiPSC-CM）开展蛋白质组学分析，结果显示二者在收缩相关机制上存在显著差异。据此，本研究借助肌调蛋白额外缺失与肌调蛋白过表达的细胞模型，探究了肌调蛋白在维持DMD来源hiPSC-CM电生理特性中的作用。研究结果表明，DMD hiPSC-CM存在钙处理紊乱现象，该异常在DMD/UTRN敲除（knockout, KO）型hiPSC-CM中更为显著，且DMD hiPSC-CM的后超极化电位（afterhyperpolarization, AHP）数值升高。而肌调蛋白过表达可同时改善钙振荡与后超极化电位异常。本研究结果证实，肌调蛋白对于维持DMD hiPSC-CM的电生理特性具有重要意义。