RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching.
RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching.
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DOI：
10.1007/s12551-017-0267-5
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发表时间：
2018-02-01
影响因子：
--
通讯作者：
Sun, Mingming
中科院分区：
文献类型：
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作者：
Guo, Wei;Sun, Mingming
心肌病，也称为心脏肌肉疾病，是一种导致心肌收缩改变和/或心室充盈能力受损的不利状况。心肌病的发生和发展目前还没有很好的定义。肌联蛋白是一种巨大的多功能肌节丝蛋白，为心肌细胞提供被动刚度，并在心肌病和心力衰竭的发生和发展中发挥重要作用。基于钛蛋白的被动刚度可以主要通过弹簧区域中的同种型转换和翻译后修饰来调节。最近，TTN的基因突变已被确定，也可以有助于可变被动刚度，但详细的机制仍不清楚。在这篇综述中，我们将讨论肌联蛋白异构体转换，因为它涉及到选择性剪接在发展阶段和物种之间的差异和肌肉类型。我们提供了由RBM 20控制的TTN剪接的调节机制的更新，并涵盖TTN剪接在调节健康和衰竭心脏的舒张刚度和收缩顺应性中的作用。最后，本综述试图为RBM 20作为心肌病和心力衰竭药物干预的潜在靶点提供未来的方向。
Cardiomyopathy, also known as heart muscle disease, is an unfavorable condition leading to alterations in myocardial contraction and/or impaired ability of ventricular filling. The onset and development of cardiomyopathy have not currently been well defined. Titin is a giant multifunctional sarcomeric filament protein that provides passive stiffness to cardiomyocytes and has been implicated to play an important role in the origin and development of cardiomyopathy and heart failure. Titin-based passive stiffness can be mainly adjusted by isoform switching and post-translational modifications in the spring regions. Recently, genetic mutations of TTN have been identified that can also contribute to variable passive stiffness, though the detailed mechanisms remain unclear. In this review, we will discuss titin isoform switching as it relates to alternative splicing during development stages and differences between species and muscle types. We provide an update on the regulatory mechanisms of TTN splicing controlled by RBM20 and cover the roles of TTN splicing in adjusting the diastolic stiffness and systolic compliance of the healthy and the failing heart. Finally, this review attempts to provide future directions for RBM20 as a potential target for pharmacological intervention in cardiomyopathy and heart failure.