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(Circulation Research. 2004;94:201.)
© 2004 American Heart Association, Inc.

Cellular Biology

Morphological and Functional Alterations in Ventricular Myocytes From Male Transgenic Mice With Hypertrophic Cardiomyopathy

M. Charlotte Olsson, Bradley M. Palmer, Brian L. Stauffer, Leslie A. Leinwand, Russell L. Moore

From the Department of Integrative Physiology (M.C.O., B.M.P., R.L.M.), Department of Molecular, Cellular, and Developmental Biology (B.L.S., L.A.L), University of Colorado, Boulder, Colo. The present address for M.C.O. is the Department of Neuroscience, Neurophysiology, University of Uppsala, Uppsala, Sweden; and B.M.P. is at the Department of Molecular Physiology and Biophysics, University of Vermont, College of Medicine, Burlington, Vt.

Correspondence to Russell L. Moore, PhD, Department of Integrative Physiology, Campus Box 354, University of Colorado, Boulder, CO 80309-0354. E-mail rmoore{at}spot.colorado.edu

Familial hypertrophic cardiomyopathy (FHC) is a human genetic disorder caused by mutations in sarcomeric proteins. It is generally characterized by cardiac hypertrophy, fibrosis, and myocyte disarray. A transgenic mouse model of FHC with mutations in the actin-binding domain of the -myosin heavy chain (MyHC) gene displays many phenotypes similar to human FHC. At 4 months, male transgenic (TG) mice present with concentric cardiac hypertrophy that progresses to dilation with age. Accompanying this latter morphological change is systolic and diastolic dysfunction. Left ventricular (LV) myocytes from male TG and wild-type (WT) littermates at 5 and 12 months of age were isolated and used for morphological and functional studies. Myocytes from 5- and 12-month-old TG animals had shorter sarcomere lengths compared with WT. This sarcomere length difference was abolished in the presence of 2,3-butanedione monoxime, suggesting that the basal level of contractile element activation was increased in TG myocytes. Myocytes from 12-month-old TG mice were significantly longer than those from age-matched WT controls, and TG myocytes exhibited Z-band disorganization. When cells were paced at 0.5 Hz, TG myocyte relengthening and the fall in intracellular [Ca²⁺] were slowed when compared with cells from age-matched WT controls. Moreover, an increased amount of ß-myosin heavy chain protein was found in hearts from TG compared with WT. Thus, myocytes from the -MyHC TG mouse model display many morphological and functional abnormalities that may help explain the LV dysfunction seen in this TG mouse model of FHC.

Key Words: 2,3-butanedione monoxime • calcium • relaxation • heart failure

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