Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart.
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 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. This increase in beta-tropomyosin message and protein causes a concomitant decrease in the level of alpha-tropomyosin transcripts and their associated protein. There is a preferential formation of the alpha beta-heterodimer in the transgenic mouse myofibrils, and there are no detectable alterations in the expression of other contractile protein genes, including the endogenous beta-tropomyosin isoform. When expression from the beta-tropomyosin transgene is terminated, alpha-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 alpha- and beta-tropomyosin gene expression in the murine heart, which results in a functional correlation between alpha- and beta-tropomyosin isoform content and cardiac performance.
Muthuchamy
M
M
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Ohio 45267, USA.
Grupp
I L
IL
Grupp
G
G
O'Toole
B A
BA
Kier
A B
AB
Boivin
G P
GP
Neumann
J
J
Wieczorek
D F
DF
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D003285:Contractile Proteins / Q000096:biosynthesis; D017931:DNA Primers; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D012518:Sarcomeres / Q000502:physiology / Q000648:ultrastructure; D014335:Tropomyosin / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D003285:Contractile Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D014335:Tropomyosin