Cardiac myosin-binding protein C (cMyBP-C) is a sarcomeric protein that dynamically regulates thick-filament structure and function. In constitutive cMyBP-C knockout (cMyBP-C^−/−) mice, loss of cMyBP-C has been linked to left ventricular dilation, cardiac hypertrophy, and systolic and diastolic dysfunction, although the pathogenesis of these phenotypes remains unclear.

We generated cMyBP-C conditional knockout (cMyBP-C-cKO) mice expressing floxed cMyBP-C alleles and a tamoxifen-inducible Cre-recombinase fused to 2 mutated estrogen receptors to study the onset and progression of structural and functional phenotypes caused by the loss of cMyBP-C. In adult cMyBP-C-cKO mice, knockdown of cMyBP-C over a 2-month period resulted in a corresponding impairment of diastolic function and a concomitant abbreviation of systolic ejection, although contractile function was largely preserved. No significant changes in cardiac structure or morphology were immediately evident; however, mild hypertrophy developed after near-complete knockdown of cMyBP-C. In response to pressure overload induced by transaortic constriction, cMyBP-C-cKO mice treated with tamoxifen also developed greater cardiac hypertrophy, left ventricular dilation, and reduced contractile function.

These results indicate that myocardial dysfunction is largely caused by the removal of cMyBP-C and occurs before the onset of cytoarchitectural remodeling in tamoxifen-treated cMyBP-C-cKO myocardium. Moreover, near ablation of cMyBP-C in adult myocardium primarily leads to the development of hypertrophic cardiomyopathy in contrast to the dilated phenotype evident in cMyBP-C^−/− mice, which highlights the importance of additional factors such as loading stress in determining the expression and progression of cMyBP-C–associated cardiomyopathy.