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Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice
Samantha P Harris1, Christopher R Bartley, Timothy A Hacker
1Department of Physiology, Section of Cardiovascular Medicine, University of Wisconsin Medical School, Madison, Wis 53706, USA. spharris@physiology.wisc.edu
Insights
Familial hypertrophic cardiomyopathy (FHC) is an inherited heart disease. Eliminating cardiac myosin binding protein-C (cMyBP-C) in mice caused significant cardiac hypertrophy and impaired heart function, revealing cMyBP-C
Area of Science:
- Cardiovascular Biology
- Genetics
- Molecular Medicine
Background:
- Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder affecting heart muscle.
- Mutations in myosin binding protein-C (MyBP-C) account for a significant portion of FHC cases.
- The precise function of MyBP-C in FHC pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of cardiac myosin binding protein-C (cMyBP-C) in cardiac function and development.
- To determine the consequences of cMyBP-C absence using a genetically engineered mouse model.
Main Methods:
- Gene targeting was employed to create a knockout mouse model lacking cMyBP-C.
- Western blot analysis confirmed the absence of cMyBP-C in knockout mouse hearts.
- Cardiac function was assessed using echocardiography and myocyte contractility measurements.
Main Results:
- Mice lacking cMyBP-C (homozygous knockout) developed significant cardiac hypertrophy.
- Homozygous knockout mice exhibited impaired diastolic and systolic cardiac function.
- Reduced calcium sensitivity of tension was observed in myocytes from knockout mice.
Conclusions:
- Cardiac myosin binding protein-C is not essential for normal cardiac development.
- The absence of cMyBP-C leads to pronounced cardiac hypertrophy and functional deficits.
- This study provides critical insights into the role of cMyBP-C in maintaining cardiac health.
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.