Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy

• DOI: 10.1007/s00109-016-1483-3
• Publication Date: 2016-11-26T08:32:55Z
• Authors: Florian Hinze; Christoph Dieterich; Michael H. Radke; Henk Granzier; Michael Gotthardt
• Keywords: Heart Failure; Male; Mice, Knockout; 0301 basic medicine; Heart Ventricles; Myocardium; Intracellular Signaling Peptides and Proteins; Muscle Proteins; RNA-Binding Proteins; Cardiomegaly; Stroke Volume; LIM Domain Proteins; 3. Good health; Mice; 03 medical and health sciences; Gene Expression Regulation; Cardiovascular and Metabolic Diseases; Diastole; Animals; Humans; Original Article; Collagen; Protein Kinases; Signal Transduction

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.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.