Guo Wei, Sun Mingming
Animal Science, University of Wyoming, Laramie, WY, 82071, USA.
Center for Cardiovascular Research and Integrative Medicine, University of Wyoming, Laramie, WY, 82071, USA.
Biophys Rev. 2018 Feb;10(1):15-25. doi: 10.1007/s12551-017-0267-5. Epub 2017 Jun 2.
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.
心肌病，也被称为心肌疾病，是一种导致心肌收缩改变和/或心室充盈能力受损的不良状况。目前，心肌病的发病和发展尚未完全明确。肌联蛋白是一种巨大的多功能肌节细丝蛋白，它为心肌细胞提供被动弹性，并且被认为在心肌病和心力衰竭的起源与发展中起重要作用。基于肌联蛋白的被动弹性主要可通过弹簧区域的异构体切换和翻译后修饰来调节。最近，已鉴定出TTN的基因突变，其也可导致可变的被动弹性，尽管详细机制仍不清楚。在本综述中，我们将讨论肌联蛋白异构体切换，因为它与发育阶段的可变剪接以及物种和肌肉类型之间的差异有关。我们提供了由RBM20控制的TTN剪接调控机制的最新信息，并阐述了TTN剪接在调节健康心脏和衰竭心脏的舒张弹性和收缩顺应性中的作用。最后，本综述试图为RBM20作为心肌病和心力衰竭药理干预的潜在靶点提供未来方向。
