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