Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) lack nanoscale structures essential for efficient excitation–contraction coupling. Such nanostructures, known as dyads, are frequently disrupted in heart failure. Here we show that the reduced expression of cardiomyopathy-associated 5 (CMYA5), a master protein that establishes dyads, contributes to dyad disorganization in heart failure and to impaired dyad assembly in hiPSC-CMs, and that a miniaturized form of CMYA5 suitable for delivery via an adeno-associated virus substantially improved dyad architecture and normalized cardiac function under pressure overload. In hiPSC-CMs, the miniaturized form of CMYA5 increased contractile forces, improved Ca²⁺ handling and enhanced the alignment of sarcomere Z-lines with ryanodine receptor 2, a protein that mediates the sarcoplasmic release of stored Ca²⁺. Our findings clarify the mechanisms responsible for impaired dyad structure in diseased cardiomyocytes, and suggest strategies for promoting dyad assembly and stability in heart disease and during the derivation of hiPSC-CMs.

源自人诱导多能干细胞 （hiPSC-CM） 的心肌细胞缺乏有效兴奋-收缩耦合所必需的纳米级结构。这种纳米结构被称为二元组，在心力衰竭中经常被破坏。在这里，我们表明心肌病相关 5 （CMYA5） 的表达降低，CMYA5 是一种建立二元的主蛋白，导致心力衰竭中的二元组织混乱和 hiPSC-CMs 中的二元组装受损，并且适合通过腺相关病毒递送的 CMYA5 的小型化形式显着改善了二元结构，并在压力超负荷下使心脏功能正常化。在 hiPSC-CMs 中，CMYA5 的小型化形式增加了收缩力，改善了 Ca²⁺ 处理，并增强了肌节 Z 线与兰尼碱受体 2 的对齐，兰尼碱受体 2 是一种介导储存的 Ca²⁺ 的肌浆释放的蛋白质。我们的研究结果阐明了导致患病心肌细胞二元结构受损的机制，并提出了在心脏病和 hiPSC-CMs 衍生过程中促进二元组装和稳定性的策略。