Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation

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...

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Veröffentlicht in:The Journal of biological chemistry 2001-02, Vol.276 (6), p.3743-3755
Hauptverfasser: Miller, Todd, Szczesna, Danuta, Housmans, Philippe R., Zhao, Jiaju, de Freitas, Fatima, Gomes, Aldrin V., Culbreath, Lieneke, McCue, Jessica, Wang, Yi, Xu, Yuanyuan, Kerrick, W. Glenn L., Potter, James D.
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container_issue 6
container_start_page 3743
container_title The Journal of biological chemistry
container_volume 276
creator Miller, Todd
Szczesna, Danuta
Housmans, Philippe R.
Zhao, Jiaju
de Freitas, Fatima
Gomes, Aldrin V.
Culbreath, Lieneke
McCue, Jessica
Wang, Yi
Xu, Yuanyuan
Kerrick, W. Glenn L.
Potter, James D.
description 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 α-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 rateg. 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.
doi_str_mv 10.1074/jbc.M006746200
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subjects Animals
Base Sequence
Body Weight
Cardiomyopathies - genetics
Cardiomyopathies - physiopathology
DNA Primers
Heart - physiopathology
Humans
Mice
Mice, Transgenic
Mutation
Organ Size
Physical Conditioning, Animal
Troponin T - genetics
Troponin T - physiology
title Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation
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