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Cardiac myosin heavy chains lacking the light chain binding domain cause hypertrophic cardiomyopathy in mice
R E Welikson1, S H Buck, J R Patel
1Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
Insights
Altering cardiac myosin
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Familial hypertrophic cardiomyopathy (HCM) is a dominantly inherited heart disease.
- Over 40 mutations in the cardiac myosin heavy chain (MHC) gene and mutations in myosin light chains are linked to HCM.
- The biochemical basis of HCM and how mutations lead to disease remain poorly understood.
Purpose of the Study:
- To investigate the role of myosin's force transmission in cardiac muscle.
- To test the hypothesis that altering the lever arm of MHC can induce dominant mutations in cardiac muscle.
- To determine if changes in myosin force transmission are sufficient to cause HCM.
Main Methods:
- Generated transgenic mice expressing a mutant cardiac myosin heavy chain (MHC) with a removed light chain binding domain.
- Assessed cardiac morphology and histology in transgenic mice.
- Evaluated myocyte function, including Ca2+ sensitivity of tension and relaxation rates, in skinned myocytes and multicellular preparations.
Main Results:
- Transgenic mice exhibited asymmetric cardiac hypertrophy, primarily in the anterior wall.
- Histological analysis revealed cellular hypertrophy, myocyte disorganization, small vessel coronary disease, and valvular pathology.
- Myocytes from transgenic hearts showed decreased Ca2+ sensitivity of tension and impaired relaxation.
Conclusions:
- Alterations in myosin force transmission are sufficient to induce hypertrophic cardiomyopathy.
- This study provides evidence that impaired force transmission, not just catalytic function, can lead to HCM.
- Findings highlight the critical role of myosin's mechanical properties in cardiac health.
Abstract:
Myosin is a chemomechanical motor that converts chemical energy into the mechanical work of muscle contraction. More than 40 missense mutations in the cardiac myosin heavy chain (MHC) gene and several mutations in the two myosin light chains cause a dominantly inherited heart disease called familial hypertrophic cardiomyopathy. Very little is known about the biochemical defects in these alleles and how the mutations lead to disease. Because removal of the light chain binding domain in the lever arm of MHC should alter myosin's force transmission but not its catalytic function, we tested the hypothesis that such a mutant MHC would act as a dominant mutation in cardiac muscle. Hearts from transgenic mice expressing this mutant myosin are asymmetrically hypertrophied, with increases in mass primarily restricted to the cardiac anterior wall. Histological examination demonstrates marked cellular hypertrophy, myocyte disorganization, small vessel coronary disease, and severe valvular pathology that included thickening and plaque formation. Skinned myocytes and multicellular preparations from transgenic hearts exhibited decreased Ca2+ sensitivity of tension and decreased relaxation rates after flash photolysis of diazo 2. These experiments demonstrate that alterations in myosin force transmission are sufficient to trigger the development of hypertrophic cardiomyopathy.