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 alpha-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 Ca(2+) 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 Ca(2+) dependence of force; and 6) computer simulations that reproduced experimental observations and suggested that the I79N mutation decreases the apparent off rate of Ca(2+) 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.
Miller
T
T
University of Miami School of Medicine, Departments of Molecular and Cellular Pharmacology and Physiology and Biophysics, Miami, Florida 33136 and the Department of Anesthesiology, Mayo Foundation, Rochester, Minnesota 55905.
Szczesna
D
D
Housmans
P R
PR
Zhao
J
J
de Freitas
F
F
Gomes
A V
AV
Culbreath
L
L
McCue
J
J
Wang
Y
Y
Xu
Y
Y
Kerrick
W G
WG
Potter
J D
JD
D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology*; D017931:DNA Primers; D006321:Heart / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009929:Organ Size; D010805:Physical Conditioning, Animal; D020107:Troponin T / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D020107:Troponin T