Elimination of cardiac myosin binding protein-C in knockout mice resulted in profound cardiac hypertrophy and significantly depressed indices of diastolic and systolic function.
Does the elimination of cardiac MyBP-C cause cardiac hypertrophy and impaired contractile function in a mouse model?
The creation of a cMyBP-C knockout mouse model demonstrates that the absence of this protein leads to profound cardiac hypertrophy and impaired contractile function, mimicking aspects of familial hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (FHC) is an inherited autosomal dominant disease caused by mutations in sarcomeric proteins. Among these, mutations that affect myosin binding protein-C (MyBP-C), an abundant component of the thick filaments, account for 20% to 30% of all mutations linked to FHC. However, the mechanisms by which MyBP-C mutations cause disease and the function of MyBP-C are not well understood. Therefore, to assess deficits due to elimination of MyBP-C, we used gene targeting to produce a knockout mouse that lacks MyBP-C in the heart. Knockout mice were produced by deletion of exons 3 to 10 from the endogenous cardiac (c) MyBP-C gene in murine embryonic stem (ES) cells and subsequent breeding of chimeric founder mice to obtain mice heterozygous (+/-) and homozygous (-/-) for the knockout allele. Wild-type (+/+), cMyBP-C(+/-), and cMyBP-C(-/-) mice were born in accordance with Mendelian inheritance ratios, survived into adulthood, and were fertile. Western blot analyses confirmed that cMyBP-C was absent in hearts of homozygous knockout mice. Whereas cMyBP-C(+/-) mice were indistinguishable from wild-type littermates, cMyBP-C(-/-) mice exhibited significant cardiac hypertrophy. Cardiac function, assessed using 2-dimensionally guided M-mode echocardiography, showed significantly depressed indices of diastolic and systolic function only in cMyBP-C(-/-) mice. Ca2+ sensitivity of tension, measured in single skinned myocytes, was reduced in cMyBP-C(-/-) but not cMyBP-C(+/-) mice. These results establish that cMyBP-C is not essential for cardiac development but that the absence of cMyBP-C results in profound cardiac hypertrophy and impaired contractile function.
Harris et al. (2002) studied Familial hypertrophic cardiomyopathy. Cardiac MyBP-C knockout (-/-) vs. Wild-type (+/+) and heterozygous (+/-) mice was evaluated on Cardiac hypertrophy and function. Elimination of cardiac myosin binding protein-C in knockout mice resulted in profound cardiac hypertrophy and significantly depressed indices of diastolic and systolic function.
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