Abnormal contractile function in transgenic mice expressing a familial hypeptrophic 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 s tudy 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 tran sgenic I79N lines compared with wild type and/or nontransgenic mice demonst rated: 1) normal survival and no cardiac hypertrophy even with chronic exer cise; 2) large increases in Ca2+ sensitivity of ATPase activity and force i n 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/cr oss-sectional area and ATPase activity; 5) loss of sensitivity to pH-induce d shifts in the Ca2+ dependence of force; and 6) computer simulations that reproduced experimental observations and suggested that the I79N mutation d ecreases the apparent off rate of Ca2+ from troponin C and increases cross- bridge detachment rate g. Simulations for intact living fibers predict a hi gher basal contractility, a faster rate of force development, slower relaxa tion, 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.