Abstract
Diminished cardiac contractile function is a characteristic feature of dilated cardiomyopathy (DCM) and many other heart failure (HF) causing etiologies. We tested the hypothesis that targeting the sarcomere to increase cardiac contractility can effectively prevent the DCM phenotype in muscle-LIM protein knockout (MLP(-/-)) mice. The ablation of cardiac myosin binding protein C (MYBPC3(-/-)) protected the MLP(-/-) mice from developing the DCM phenotype. We examined the in vivo cardiac function and morphology of the resultant mouse model lacking both MLP and MYBPC3 (DKO) by echocardiography and pressure-volume catheterization and found a significant reduction in hypertrophy, as evidenced by normalized wall thickness and chamber dimensions, and improved systolic function, as evidenced by enhanced ejection fraction (~26% increase compared MLP(-/-) mice) and rate of pressure development (DKO 7851.0 ± 504.8 vs. MLP(-/-) 4496.4 ± 196.8 mmHg/s). To investigate the molecular basis for the improved DKO phenotype we performed mechanical experiments in skinned myocardium isolated from WT and the individual KO mice. Skinned myocardium isolated from DKO mice displayed increased Ca(2+) sensitivity of force generation, and significantly accelerated rate of cross-bridge detachment (+63% compared to MLP(-/-)) and rate of XB recruitment (+58% compared to MLP(-/-)) at submaximal Ca(2+) activations. The in vivo and in vitro functional enhancement of DKO mice demonstrates that enhancing the sarcomeric contractility can be cardioprotective in HF characterized by reduced cardiac output, such as in cases of DCM.