Journal
CIRCULATION RESEARCH
Volume 90, Issue 5, Pages 594-601Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000012222.70819.64
Keywords
myosin binding protein-C; heart; myocardium; gene knockout; sarcomeric proteins
Funding
- NHLBI NIH HHS [P01- HL47053] Funding Source: Medline
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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 gone 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.
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