β-Tropomyosin Overexpression Induces Severe Cardiac Abnormalities

Abstract

Tropomyosin, a coiled-coil dimer, stabilizes actin filaments and is central to the control of calcium-regulated striated muscle contraction. Striated muscle-specificα-tropomyosin is the predominant isoform in cardiac muscle, with low levels ofβ-tropomyosin restricted to fetal development in the mouse. To understand the functional role of various tropomyosin isoforms during myofilament activation and regulation in the intact sarcomere, we generated transgenic mice that overexpress striated muscle-specificβ-tropomyosin in the adult heart. Our earlier results succinctly demonstrate that overexpression ofβ-tropomyosin in the hearts of transgenic mice decreases endogeneousα-tropomyosin levels while altering diastolic function of the myocardium. To explore further the significance of altering theα- toβ-tropomyosin isoform ratio in developing murine myocardium, we generated transgenic mice which expressβ-tropomyosin at high levels in the heart. The data show that higher levels ofβ-tropomyosin expression are lethal with death ensuing between 10–14 days postnatally. A detailed histological analysis demonstrates that the hearts of these mice exhibit several pathological abnormalities, including thrombus formation in the lumen of both atria and in the subendocardium of the left ventricle. Other changes include atrial enlargement and fibrosis, and diffuse myocytolysis, Physiological analyses using ventricular muscle strip preparations from these mice reveal that both myocardial contraction and relaxation parameters are severely impaired. Thus, these results firmly demonstrate an essential difference in tropomyosin isoform function in physiologically regulating cardiac performance.