title: Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.
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.
  
  
  
  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.
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Hinze
authors.affiliation: Klaus Tschira Institute for Integrative Computational Cardiology and Department of Cardiology, Angiology, and Pneumology, Heidelberg University, Analysezentrum III, INF 669, 69120, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dieterich
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Radke
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Arizona Health Sciences Center, 1501 N. Campbell, PO Box 245051, Tucson, AZ, 85724, USA.
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany. gotthardt@mdc-berlin.de.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany. gotthardt@mdc-berlin.de.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0003-1788-3172
authors.initials: M
authors.lastname: Gotthardt
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003971:Diastole / Q000502:physiology; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013318:Stroke Volume / Q000502:physiology
chemical_list: C486306:Fhl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C584322:RBM20 protein, mouse; D016601:RNA-Binding Proteins; D003094:Collagen; D011494:Protein Kinases; C579730:titin protein, mouse
keywords: Heart failure; Hypertrophy signaling; Mouse models; RNA processing; Therapy