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

Todd Miller, Danuta Szczesna, Philippe R. Housmans, Jiaju Zhao, Fatima De Freitas, Aldrin V Gomes, Lieneke Culbreath, Jessica McCue, Yi Wang, Yuanyuan Xu, W. Glenn L Kerrick, James D. Potter

Research output: Contribution to journalArticle

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Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)3743-3755
Number of pages13
JournalJournal of Biological Chemistry
Volume276
Issue number6
DOIs
StatePublished - Feb 9 2001
Externally publishedYes

Fingerprint

Familial Hypertrophic Cardiomyopathy
Troponin T
Transgenic Mice
Adenosine Triphosphatases
Troponin C
Mutation
Myosin Heavy Chains
Fibers
Genetically Modified Animals
Animals
Calcium-Transporting ATPases
Chemical activation
Cardiomegaly
Computer Simulation
Myocardium
Computer simulation
Animal Models
Survival
Mortality

ASJC Scopus subject areas

  • Biochemistry

Cite this

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

In: Journal of Biological Chemistry, Vol. 276, No. 6, 09.02.2001, p. 3743-3755.

Research output: Contribution to journalArticle

Miller, T, Szczesna, D, Housmans, PR, Zhao, J, De Freitas, F, Gomes, AV, Culbreath, L, McCue, J, Wang, Y, Xu, Y, Kerrick, WGL & Potter, JD 2001, 'Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation', Journal of Biological Chemistry, vol. 276, no. 6, pp. 3743-3755. https://doi.org/10.1074/jbc.M006746200
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. / Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 6. pp. 3743-3755.
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