Titin is a giant sarcomeric protein that is involved in a large number of functions, with a primary role in skeletal and cardiac sarcomere organization and stiffness. The titin gene (TTN) is subject to various alternative splicing events, but in the region that is present at the M-line, the only exon that can be spliced out is Mex5, which encodes for the insertion sequence 7 (is7). Interestingly, in the heart, the majority of titin isoforms are Mex5+, suggesting a cardiac role for is7. Here, we performed comprehensive functional, histological, transcriptomic, microscopic and molecular analyses of a mouse model lacking the Ttn Mex5 exon (ΔMex5), and revealed that the absence of the is7 is causative for dilated cardiomyopathy. ΔMex5 mice showed altered cardiac function accompanied by increased fibrosis and ultrastructural alterations. Abnormal expression of excitation-contraction coupling proteins was also observed. The results reported here confirm the importance of the C-terminal region of titin in cardiac function and are the first to suggest a possible relationship between the is7 and excitation-contraction coupling. Finally, these findings give important insights for the identification of new targets in the treatment of titinopathies.

中文翻译：

---

Titin M 线插入序列 7 是小鼠正常心脏功能所必需的。

Titin 是一种巨大的肌节蛋白，参与多种功能，在骨骼和心脏肌节的组织和僵硬中起主要作用。肌动蛋白基因 (TTN) 受到各种可变剪接事件的影响，但在 M 线存在的区域中，唯一可以剪接的外显子是 Mex5，它编码插入序列 7 (is7)。有趣的是，在心脏中，大多数肌联蛋白异构体是 Mex5+，这表明 is7 具有心脏作用。在这里，我们对缺乏 Ttn Mex5 外显子 (ΔMex5) 的小鼠模型进行了全面的功能、组织学、转录组学、显微镜和分子分析，并发现 is7 的缺失是扩张型心肌病的病因。ΔMex5 小鼠表现出心脏功能改变，伴有纤维化增加和超微结构改变。还观察到兴奋-收缩偶联蛋白的异常表达。这里报告的结果证实了肌动蛋白 C 末端区域在心脏功能中的重要性，并且是第一个提出 is7 和兴奋-收缩耦合之间可能存在的关系。最后，这些发现为确定治疗titin病的新靶点提供了重要的见解。