Molecular and physiological effects of overexpressing striated muscle β-tropomyosin in the adult murine heart

Abstract

Tropomyosins comprise a family of actin-binding proteins that are central to the control of calcium-regulated striated muscle contraction. To understand the functional role of tropomyosin isoform differences in cardiac muscle, we generated transgenic mice that overexpress striated muscle-specific β-tropomyosin in the adult heart. Nine transgenic lines show a 150-fold increase in β-tropomyosin mRNA expression in the heart, along with a 34-fold increase in the associated protein. This increase in β-tropomyosin message and protein causes a concomitant decrease in the level of α-tropomyosin transcripts and their associated protein. There is a preferential formation of the αβ-heterodimer in the transgenic mouse myofibrils, and there are no detectable alterations in the expression of other contractile protein genes, including the endogenous β-tropomyosin isoform. When expression from the β-tropomyosin transgene is terminated, α-tropomyosin expression returns to normal levels. No structural changes were observed in these transgenic hearts nor in the associated sarcomeres. Interestingly, physiological analyses of these hearts using a work-performing model reveal a significant effect on diastolic function. As such, this study demonstrates that a coordinate regulatory mechanism exists between α- and β-tropomyosin gene expression in the murine heart, which results in a functional correla-tion between α- and β-tropomyosin isoform content and cardiac performance.