Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice

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

Research output: Contribution to journalArticle

228 Citations (Scopus)

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

Fingerprint

Cardiac Myosins
Hypertrophic Cardiomyopathy
Knockout Mice
Familial Hypertrophic Cardiomyopathy
Mutation
Cardiomegaly
Gene Targeting
Embryonic Stem Cells
myosin-binding protein C
Muscle Cells
Breeding
Echocardiography
Exons
Western Blotting
Alleles

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Harris, S. ., Bartley, C. R., Hacker, T. A., McDonald, K. S., Douglas, P. S., Greaser, M. L., ... 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

Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. / Harris, Samantha -; Bartley, Christopher R.; Hacker, Timothy A.; McDonald, Kerry S.; Douglas, Pamela S.; Greaser, Marion L.; Powers, Patricia A.; Moss, Richard L.

In: Circulation Research, Vol. 90, No. 5, 22.03.2002, p. 594-601.

Research output: Contribution to journalArticle

Harris, S, Bartley, CR, Hacker, TA, McDonald, KS, Douglas, PS, Greaser, ML, Powers, PA & Moss, RL 2002, 'Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice', Circulation Research, vol. 90, no. 5, pp. 594-601. https://doi.org/10.1161/01.RES.0000012222.70819.64
Harris, Samantha - ; Bartley, Christopher R. ; Hacker, Timothy A. ; McDonald, Kerry S. ; Douglas, Pamela S. ; Greaser, Marion L. ; Powers, Patricia A. ; Moss, Richard L. / Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. In: Circulation Research. 2002 ; Vol. 90, No. 5. pp. 594-601.
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AU - McDonald, Kerry S.

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AU - Greaser, Marion L.

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AU - Moss, Richard L.

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