Alternative splicing of titin restores diastolic function in an HFpEF-like genetic murine model (Ttn ΔIAjxn)

Mathew Bull, Mei Methawasin, Joshua Strom, Pooja Nair, Kirk Hutchinson, Hendrikus "Henk" Granzier

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Rationale: Patients with heart failure with preserved ejection fraction (HFpEF) experience elevated filling pressures and reduced ventricular compliance. The splicing factor RNA-binding motif 20 (RBM20) regulates the contour length of titin's spring region and thereby determines the passive stiffness of cardiomyocytes. Inhibition of RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce passive stiffness. Objective: To determine the therapeutic potential of upregulating compliant titin isoforms in an HFpEF-like state in the mouse. Methods and Results: Constitutive and inducible cardiomyocyte-specific RBM20-inhibited mice were produced on a Ttn ΔIAjxn background to assess the effect of upregulating compliant titin at the cellular and organ levels. Genetic deletion of the I-band-A-band junction (IAjxn) in titin increases strain on the spring region and causes a HFpEF-like syndrome in the mouse without pharmacological or surgical intervention. The increased strain represents a mechanical analog of deranged post-translational modification of titin that results in increased passive myocardial stiffness in patients with HFpEF. On inhibition of RBM20 in Ttn ΔIAjxn mice, compliant titin isoforms were expressed, diastolic function was normalized, exercise performance was improved, and pathological hypertrophy was attenuated. Conclusions: We report for the first time a benefit from upregulating compliant titin isoforms in a murine model with HFpEF-like symptoms. Constitutive and inducible RBM20 inhibition improves diastolic function resulting in greater tolerance to exercise. No effective therapies exists for treating this pervasive syndrome; therefore, our data on RBM20 inhibition are clinically significant.

Original languageEnglish (US)
Pages (from-to)764-772
Number of pages9
JournalCirculation Research
Volume119
Issue number6
DOIs
StatePublished - Sep 2 2016

Keywords

  • compliance
  • diastole
  • diastolic heart failure
  • hypertrophy
  • myocardium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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