Circulation Research. 2002;90:594-601
Published online before print January 31, 2002, doi: 10.1161/01.RES.0000012222.70819.64
Published online before print January 31, 2002, doi: 10.1161/01.RES.0000012222.70819.64
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C Knockout Mice
From the Departments of Physiology (S.P.H., C.R.B., P.A.P., R.L.M.) and Medicine (T.A.H., P.S.D.), Section of Cardiovascular Medicine, University of Wisconsin Medical School, Madison, Wis; the Biotechnology Center (C.R.B., P.A.P.) and Muscle Biology Laboratory (M.L.G.), University of Wisconsin-Madison, Madison, Wis; and the Department of Physiology (K.S.M.), University of Missouri School of Medicine, Columbia, Mo.
Correspondence to Samantha P. Harris, PhD, University of Wisconsin-Madison, Dept of Physiology/109 SMI, 1300 University Ave, Madison, WI 53706. E-mail spharris{at}physiology.wisc.edu
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.
Key Words: myosin binding protein-C • heart • myocardium • gene knockout • sarcomeric proteins
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