MOLECULAR AND PHYSIOLOGICAL-EFFECTS OF OVEREXPRESSING STRIATED-MUSCLEBETA-TROPOMYOSIN IN THE ADULT MURINE HEART

Tropomyosins comprise a family of actin-binding proteins that are cent ral to the control of calcium-regulated striated muscle contraction. T o understand the functional role of tropomyosin isoform differences in cardiac muscle, we generated transgenic mice that overexpress striate d muscle-specific beta-tropomyosin in the adult heart. Nine transgenic lines show a 150-fold increase in beta-tropomyosin mRNA expression in the heart, along with a 34-fold increase in the associated protein. T his increase in beta-tropomyosin message and protein causes a concomit ant decrease in the level of alpha-tropomyosin transcripts and their a ssociated protein. There is a preferential formation of the alpha beta -heterodimer in the transgenic mouse myofibrils, and there are no dete ctable alterations in the expression of other contractile protein gene s, including the endogenous beta-tropomyosin isoform. When expression from the beta-tropomyosin transgene is terminated, alpha-tropomyosin e xpression returns to normal levels. No structural changes were observe d in these transgenic hearts nor in the associated sarcomeres. Interes tingly, physiological analyses of these hearts using a work-performing model reveal a significant effect on diastolic function. As such, thi s study demonstrates that a coordinate regulatory mechanism exists bet ween alpha and beta-tropomyosin gene expression in the murine heart, w hich results in a functional correla tion between alpha and beta-tropo myosin isoform content and cardiac performance.