Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy

Florian Hinze, Christoph Dieterich, Michael H. Radke, Hendrikus "Henk" Granzier, Michael Gotthardt

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1349-1358
Number of pages10
JournalJournal of Molecular Medicine
Volume94
Issue number12
DOIs
StatePublished - Dec 1 2016

Fingerprint

Connectin
Atrophy
Protein Isoforms
Hypertrophy
Diastole
Muscle Development
Therapeutics
Growth
Knockout Mice
Heart Diseases
Proteins
Collagen
Fatty Acids
Heart Failure
Gene Expression

Keywords

  • Heart failure
  • Hypertrophy signaling
  • Mouse models
  • RNA processing
  • Therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy. / Hinze, Florian; Dieterich, Christoph; Radke, Michael H.; Granzier, Hendrikus "Henk"; Gotthardt, Michael.

In: Journal of Molecular Medicine, Vol. 94, No. 12, 01.12.2016, p. 1349-1358.

Research output: Contribution to journalArticle

Hinze, Florian ; Dieterich, Christoph ; Radke, Michael H. ; Granzier, Hendrikus "Henk" ; Gotthardt, Michael. / Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy. In: Journal of Molecular Medicine. 2016 ; Vol. 94, No. 12. pp. 1349-1358.
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