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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Co-expression of skeletal and cardiac troponin T decreases mouse cardiac function

¹Department of Physiology and Biophysics, Case Western Reserve University, and ²Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio; ³Department of Biomedical Sciences, Florida Atlantic University, Boca Raton; and ⁴Section of Molecular Cardiology, Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, Illinois

Submitted 7 April 2007 ; accepted in final form 19 October 2007

In contrast to skeletal muscles that simultaneously express multiple troponin T (TnT) isoforms, normal adult human cardiac muscle contains a single isoform of cardiac TnT. To understand the significance of myocardial TnT homogeneity, we examined the effect of TnT heterogeneity on heart function. Transgenic mouse hearts overexpressing a fast skeletal muscle TnT together with the endogenous cardiac TnT was investigated in vivo and ex vivo as an experimental system of concurrent presence of two classes of TnT in the adult cardiac muscle.This model of myocardial TnT heterogeneity produced pathogenic phenotypes: echocardiograph imaging detected age-progressive reductions of cardiac function; in vivo left ventricular pressure analysis showed decreased myocardial contractility; ex vivo analysis of isolated working heart preparations confirmed an intrinsic decrease of cardiac function in the absence of neurohumoral influence. The transgenic mice also showed chronic myocardial hypertrophy and degeneration. The dominantly negative effects of introducing a fast TnT into the cardiac thin filaments to produce two classes of Ca²⁺ regulatory units in the adult myocardium suggest that TnT heterogeneity decreases contractile function by disrupting the synchronized action during ventricular contraction that is normally activated as an electrophysiological syncytium.

myocardial heterogeneity; transgenic mouse; echocardiography; working heart preparation

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