Titin, a sarcomeric protein expressed primarily in striated muscles, is responsible for maintaining the structure and biomechanical properties of muscle cells. Cardiac titin undergoes developmental size reduction from 3.7 megadaltons in neonates to primarily 2.97 megadaltons in the adult. This size reduction results from gradually increased exon skipping between exons 50 and 219 of titin mRNA. ...

RATIONALE RNA-binding motif protein 20 (RBM20) is essential for normal splicing of many cardiac genes, and loss of RBM20 causes dilated cardiomyopathy. Given its role in splicing, we hypothesized an important role for RBM20 in forming circular RNAs (circRNAs), a novel class of noncoding RNA molecules. OBJECTIVE To establish the role of RBM20 in the formation of circRNAs in the heart. METHOD...

An essential role of titin as a molecular ruler in sarcomerogenesis has been frequently discussed. In this study, we tested the hypothesis that the expression of titin is a prerequisite for thick filament incorporation into sarcomeres by using an antisense oligonucleotide approach to interfere with titin translation in the de-/redifferentiation model of adult rat cardiomyocytes (ARC) in long-te...

Titins are megadalton-sized filamentous polypeptides of vertebrate striated muscle. The I-band region of titin underlies the myofibrillar passive tension response to stretch. Here, we show how titins with highly diverse I-band structures and elastic properties are expressed from a single gene. The differentially expressed tandem-Ig, PEVK, and N2B spring elements of titin are coded by 158 exons,...

The poly-immunoglobulin domain region of titin, located within the elastic section of this giant muscle protein, determines the extensibility of relaxed myofibrils mainly at shorter physiological lengths. To elucidate this region's contribution to titin elasticity, we measured the elastic properties of the N-terminal I-band Ig region by using immunofluorescence/immunoelectron microscopy and myo...

RATIONALE Recently, we have shown that Ca2+-activated force generation in diaphragm single fibers is impaired in patients with mild to moderate chronic obstructive pulmonary disease (COPD). For optimal active-force generation, the passive elasticity provided by titin is indispensable. OBJECTIVES In the present study, we determined the passive-tension-length relations of single fibers of patie...

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin pro...

Titin is a giant protein spanning from the Z-disk to the M-band of the cardiac sarcomere. In the I-band titin acts as a molecular spring, contributing to passive mechanical characteristics of the myocardium throughout a heartbeat. RNA Binding Motif Protein 20 (RBM20) is required for normal titin splicing, and its absence or altered function leads to greater expression of a very large, more comp...

OBJECTIVES The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations. BACKGROUND Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility ...