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Am J Physiol Heart Circ Physiol 276: H2148-H2158, 1999;
0363-6135/99 $5.00
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Vol. 276, Issue 6, H2148-H2158, June 1999

Cardiac myosin heavy chains lacking the light chain binding domain cause hypertrophic cardiomyopathy in mice

Robert E. Welikson1, Scott H. Buck2, Jitandrakumar R. Patel3, Richard L. Moss3, Karen L. Vikstrom1, Stephen M. Factor4, Setsuya Miyata1, Howard D. Weinberger5, and Leslie A. Leinwand1

2 Department of Pediatrics and 3 Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706; 4 Department of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York 10461; 5 Department of Medicine, University of Colorado Health Sciences Center, Denver 80262; and 1 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309

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.

transgenic mice; valve disease; myosin heavy chain


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