RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching
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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.
KeywordsTitin isoform switching Alternative splicing Cardiomyopathy RBM20
This work was supported by the National Institute of Health/National Institute of General Medical Sciences (NIGMSP20GM103432); the BGIA from the American Heart Association (16BGIA27790136 to WG); the USDA National Institute of Food and Agriculture (Hatch project 1009266 to WG). The authors would like to thank Dr. Marion Greaser and Dr. Rich McCormick for their helpful comments and proofreading of the manuscript.
Compliance with ethical standards
Conflict of interest
Wei Guo declares that he has no conflict of interest. Mingming Sun declares that he has no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
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