Jeffery. W.Walker
( Department of Physiology, University of Wisconsin, Madison, WI 53706)

Troponin I(TnI) is a subunit of the thinfilament-associated troponin-tropomyosin complex involved in calcium regulation ofskeletal and cardiac muscle contraction. We deleted the cardiac isoform of troponin I(cTnI) by using gene targeting in murine embryonic stem cells to determine thedevelopmental and physiological effects of the absence of this regulatory protein. Micelacking cTnI were born healthy, with normal heart and body weight, because a fetal TnIisoform (identical to slow skeletal TnI, ssTnI) compensated for the absence of cTnI.Compensation was only temporary, however, as 15 days after birth ssTnI expression began asteady decline, giving rise to a TnI deficiency. Mice died of acute heart failure on day18, demonstrating that some form of TnI is required for normal cardiac function andsurvival. Ventricular myocytes isolated from these TnI-depleted hearts displayed shortenedsarcomeres and elevated resting tension measured under relaxing conditions. The resultsshow that cTnI depletion alters specific mechanical properties of myocardium and can leadto a lethal from of acute heart failure. In addition, we have investigated the mechanismunderlying the down-regulation of fetal TnI gene expression during heart development byusing the cTnI mice with hypo-or hyper-thyroid status. Overall, the results indicatethat inactivation of the ssTnI gene occurs even in the absence of cTnI mRNA and proteinindicating that these are not critical signals for ssTnI down-regulation in the heart. Incontrast, thyroid hormone influences the time course of ssTnI expression and may thereforeplay a role in ssTnI inactivation during heart development.

* Supported by a Grant-in-Aid from National American HeartAssociation (Xupei. Huang Larry.F.Lemanski Jeffery. W.Walker)