Upregulating compliant titins in Rbm20(ΔRRM) mice reduced diastolic chamber stiffness and increased exercise capacity in heterozygous mice, despite depressing end-systolic elastance.
Does upregulating compliant titins via RBM20 manipulation improve diastolic function and exercise capacity in a mouse model?
Upregulating compliant titins via RBM20 manipulation reduces diastolic chamber stiffness and improves exercise capacity, suggesting a potential therapeutic target for heart failure with diastolic dysfunction despite some depression of systolic function.
BACKGROUND: Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography. METHODS AND RESULTS: Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20(ΔRRM)mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20(ΔRRM)mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20(ΔRRM) hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20(ΔRRM) mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice. CONCLUSIONS: Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.
Methawasin et al. (Thu,) conducted a other in Pathological diastolic stiffness / Heart failure. Deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20(ΔRRM) mice) was evaluated on Diastolic stiffness, Frank-Starling Mechanism, and exercise capacity. Upregulating compliant titins in Rbm20(ΔRRM) mice reduced diastolic chamber stiffness and increased exercise capacity in heterozygous mice, despite depressing end-systolic elastance.