Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.

Florian Hinze,Henk Granzier,Christoph Dieterich,Michael Gotthardt,Michael H Radke

doi:10.1007/s00109-016-1483-3

Abstract

Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin’s elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction.Key message Increasing the length of titin isoforms improves ventricular filling in heart disease.FHL proteins are regulated via RBM20 and adapt cardiac growth.RBM20 is a therapeutic target in diastolic dysfunction. Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-016-1483-3) contains supplementary material, which is available to authorized users.

Highlights

Cardiovascular disease is the main cause of death worldwide with increasing prevalence of heart failure [1]
We bred the N2B-KO as an animal model with diastolic dysfunction [5] with the splice-deficient RNA binding motif 20 (RBM20) knockout mouse lacking the RNA-binding domain (RBM20ΔRRM)
The animals display normal pre- and postnatal development, fertility, and weight gain (Supplemental Fig. S1a, b). We refer to these animals as Bsplice-rescue^ mice (N2B-KO RBM20-HET; Fig. 1a)

Summary

Introduction

Cardiovascular disease is the main cause of death worldwide with increasing prevalence of heart failure [1]. Multiple environmental and genetic factors contribute to heart failure including age, sex, diabetes, kidney disease, inflammation, and mutations in sarcomeric proteins such as titin or cardiac splice factors such as the RNA binding motif 20 (RBM20) that regulates titin-based stiffness [2]. The giant sarcomeric protein titin contributes to the diastolic properties of the heart. Titin undergoes extensive posttranslational modifications and alternative splicing adapts its elastic properties to the demands of the organism [3, 4]. The elastic PEVK and N2B regions support diastolic function, while differentially affecting cardiac growth [5, 6]. The PEVK region serves as an entropic spring, while the N2B region improves efficiency of the cardiac cycle

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Results

Conclusion