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

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.