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Published on: August 12, 2010
Dissociation of structural and functional phenotypes in cardiac myosin-binding protein C conditional knockout mice
Peter P Chen1, Jitandrakumar R Patel, Patricia A Powers
1Department of Cellular and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, 601 Science Dr, Madison, WI 53711, USA.
Background:
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.
Methods And Results:
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.
Conclusions:
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.
Insights
Loss of cardiac myosin-binding protein C (cMyBP-C) impairs heart function before structural changes occur. In adult mice, cMyBP-C loss leads to hypertrophic cardiomyopathy, unlike the dilated form seen in constitutive knockouts.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Cardiac myosin-binding protein C (cMyBP-C) is crucial for sarcomere structure and function.
- Constitutive cMyBP-C knockout mice exhibit cardiac dysfunction, but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the temporal relationship between cMyBP-C loss and cardiac dysfunction.
- To elucidate the role of cMyBP-C in the development of cardiac remodeling and cardiomyopathy.
Main Methods:
- Generated cMyBP-C conditional knockout (cMyBP-C-cKO) mice using tamoxifen-inducible Cre-recombinase.
- Administered tamoxifen to induce cMyBP-C knockdown in adult mice.
- Assessed cardiac structure, function, and response to pressure overload (transaortic constriction).
Main Results:
- Adult cMyBP-C knockdown impaired diastolic function and systolic ejection within two months.
- Cardiac structure remained largely unchanged initially, with mild hypertrophy developing upon near-complete cMyBP-C ablation.
- Under pressure overload, cMyBP-C-cKO mice showed exacerbated hypertrophy, dilation, and reduced contractile function.
Conclusions:
- Myocardial dysfunction due to cMyBP-C removal precedes observable cytoarchitectural remodeling.
- Near-complete cMyBP-C ablation in adult hearts primarily induces hypertrophic cardiomyopathy.
- Loading conditions significantly influence the progression of cMyBP-C-associated cardiomyopathy, contrasting with constitutive knockout phenotypes.
