RBM20, a potential target for treatment of cardiomyopathy via titin isoform switching

Cardiomyopathy, also known as heart muscle dis- ease, is an unfavorable condition leading to alterations in myo- cardial contraction and/or impaired ability of ventricular fill- ing. 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 ad- justed by isoform switching and post-translational modifica- tions in the spring regions. Recently, genetic mutations of TTN have been identified that can also contribute to variable pas- sive 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 con- trolled 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.