Lu Fujian, Liou Carter, Ma Qing, Wu Zexuan, Xue Bingqing, Xia Yu, Xia Shutao, Trembley Michael A, Ponek Anna, Xie Wenjun, Shani Kevin, Bortolin Raul H, Prondzynski Maksymilian, Berkson Paul, Zhang Xiaoran, Naya Francisco J, Bedi Kenneth C, Margulies Kenneth B, Zhang Donghui, Parker Kevin K, Pu William T
Institutes of Biomedical Sciences, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
Nat Biomed Eng. 2025 May;9(5):730-741. doi: 10.1038/s41551-024-01253-z. Epub 2024 Sep 5.
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 Ca handling and enhanced the alignment of sarcomere Z-lines with ryanodine receptor 2, a protein that mediates the sarcoplasmic release of stored Ca. 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.
源自人类诱导多能干细胞的心肌细胞（hiPSC-CMs）缺乏高效兴奋-收缩偶联所必需的纳米级结构。这种被称为二联体的纳米结构在心力衰竭中经常遭到破坏。在此，我们表明，心肌病相关蛋白5（CMYA5）的表达降低会导致心力衰竭中二联体结构紊乱以及hiPSC-CMs中二联体组装受损，CMYA5是一种形成二联体的主要蛋白；并且一种适合通过腺相关病毒递送的小型化形式的CMYA5可显著改善压力超负荷下的二联体结构并使心脏功能正常化。在hiPSC-CMs中，小型化形式的CMYA5增加了收缩力，改善了钙处理，并增强了肌节Z线与兰尼碱受体2的对齐，兰尼碱受体2是一种介导储存钙的肌浆释放的蛋白。我们的研究结果阐明了患病心肌细胞中二联体结构受损的机制，并提出了促进心脏病中以及hiPSC-CMs衍生过程中二联体组装和稳定性的策略。
