Alternative Splicing of Titin Restores Diastolic Function in a HFpEF-like Genetic Murine Model (TtnΔIAjxn)
Rationale: HFpEF patients experience elevated filling pressures and reduced ventricular compliance. The splicing factor 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 a HFpEF-like state in the mouse.
Methods and Results: Constitutive and inducible cardiomyocyte specific RBM20 inhibited mice were produced on a TtnΔIAjxn 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 analogue of deranged post-translational modification of titin that results in increased passive myocardial stiffness in HFpEF patients. Upon inhibition of RBM20 in TtnΔIAjxn mice, compliant titin isoforms were expressed and diastolic function was normalized, exercise performance was improved and pathologic 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.
- Received April 13, 2016.
- Revision received July 27, 2016.
- Accepted July 28, 2016.