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J. Biol. Chem., Vol. 276, Issue 6, 3743-3755, February 9, 2001
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From the University of Miami School of Medicine,
Departments of This study characterizes a transgenic animal
model for the troponin T (TnT) mutation (I79N) associated with familial
hypertrophic cardiomyopathy. To study the functional consequences of
this mutation, we examined a wild type and two I79N-transgenic mouse
lines of human cardiac TnT driven by a murine
Abnormal Contractile Function in Transgenic Mice Expressing a
Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N)
Mutation*
,,,,,,,
Molecular and Cellular Pharmacology and
¶ Physiology and Biophysics, Miami, Florida 33136 and the
§ Department of Anesthesiology, Mayo Foundation,
Rochester, Minnesota 55905
-myosin heavy chain
promoter. Extensive characterization of the transgenic I79N lines
compared with wild type and/or nontransgenic mice demonstrated: 1)
normal survival and no cardiac hypertrophy even with chronic exercise; 2) large increases in Ca2+ sensitivity of ATPase
activity and force in skinned fibers; 3) a substantial increase in the
rate of force activation and an increase in the rate of force
relaxation; 4) lower maximal force/cross-sectional area and ATPase
activity; 5) loss of sensitivity to pH-induced shifts in the
Ca2+ dependence of force; and 6) computer simulations that
reproduced experimental observations and suggested that the I79N
mutation decreases the apparent off rate of Ca2+ from
troponin C and increases cross-bridge detachment rate
g. Simulations for intact living fibers predict a higher
basal contractility, a faster rate of force development, slower
relaxation, and increased resting tension in transgenic I79N myocardium
compared with transgenic wild type. These mechanisms may contribute to
mortality in humans, especially in stimulated contractile states.
*
This work was supported by National Institutes of Health
Grants AR-45391 and HL-42325 (to J. D. P.), GM-36365 (to
P. R. H.), and AR-40906 (to W. G. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Molecular
and Cellular Pharmacology, University of Miami School of Medicine, 1600 N.W. 10th Ave., Miami, FL 33136. Tel.: 305-243-5874; Fax: 305-243-6233; E-mail: jdpotter@miami.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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