Cardiac troponin I gene knockout - A mouse model of myocardial troponin I deficiency

Troponin I is a subunit of the thin filament-associated troponin-tropomyosi n complex involved in calcium regulation of skeletal and cardiac muscle con traction. We deleted the cardiac isoform of troponin I by using gene target ing in murine embryonic stem cells to determine the developmental and physi ological effects of the absence of this regulatory protein. Mice lacking ca rdiac troponin I were born healthy, with normal heart and body weight, beca use a fetal troponin I isoform (identical to slow skeletal troponin I) comp ensated for the absence of cardiac troponin I. Compensation was only tempor ary, however, as 15 days after birth slow skeletal troponin I expression be gan 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 i s required for normal cardiac function and survival. Ventricular myocytes i solated from these troponin I-depleted hearts displayed shortened sarcomere s and elevated resting tension measured under relaxing conditions and had a reduced myofilament Ca sensitivity under activating conditions. The result s show that (1) developmental downregulation of slow skeletal troponin I oc curs even in the absence of cardiac troponin I and (2) the resultant tropon in I depletion alters specific mechanical properties of myocardium and can lead to a lethal form of acute heart failure.