© 1999 American Heart Association, Inc.
Original Contribution |
Cardiac Troponin I Gene Knockout
A Mouse Model of Myocardial Troponin I Deficiency
From the Department of Physiology, University of Wisconsin, Madison, Wis. The current affiliation for Dr Gregg is the Departments of Biochemistry and Ophthalmology, University of Louisville, Louisville, Ky.
Correspondence to Dr Jeffery W. Walker, Department of Physiology, 1300 University Ave, Madison, WI 53706. E-mail jwalker{at}physiology.wisc.edu
Abstract—Troponin I is a subunit of the thin filament–associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. We deleted the cardiac isoform of troponin I by using gene targeting in murine embryonic stem cells to determine the developmental and physiological effects of the absence of this regulatory protein. Mice lacking cardiac troponin I were born healthy, with normal heart and body weight, because a fetal troponin I isoform (identical to slow skeletal troponin I) compensated for the absence of cardiac troponin I. Compensation was only temporary, however, as 15 days after birth slow skeletal troponin I expression began a steady decline, giving rise to a troponin I deficiency. Mice died of acute heart failure on day 18, demonstrating that some form of troponin I is required for normal cardiac function and survival. Ventricular myocytes isolated from these troponin I–depleted hearts displayed shortened sarcomeres and elevated resting tension measured under relaxing conditions and had a reduced myofilament Ca sensitivity under activating conditions. The results show that (1) developmental downregulation of slow skeletal troponin I occurs even in the absence of cardiac troponin I and (2) the resultant troponin I depletion alters specific mechanical properties of myocardium and can lead to a lethal form of acute heart failure.
Key Words: ischemia • heart failure • cardiac development
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