Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice

Samantha P. Harris, Christopher R. Bartley, Timothy A. Hacker, Kerry S. McDonald, Pamela S. Douglas, Marion L. Greaser, Patricia A. Powers, Richard L. Moss

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)594-601
Number of pages8
JournalCirculation research
Volume90
Issue number5
DOIs
StatePublished - Mar 22 2002
Externally publishedYes

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Keywords

  • Gene knockout
  • Heart
  • Myocardium
  • Myosin binding protein-C
  • Sarcomeric proteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Harris, S. P., Bartley, C. R., Hacker, T. A., McDonald, K. S., Douglas, P. S., Greaser, M. L., Powers, P. A., & Moss, R. L. (2002). Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circulation research, 90(5), 594-601. https://doi.org/10.1161/01.RES.0000012222.70819.64