© 1998 American Heart Association, Inc.
Original Contributions |
Altered Expression of Tropomodulin in Cardiomyocytes Disrupts the Sarcomeric Structure of Myofibrils
From the Department of Biochemistry and Molecular Biology and the Institute for Genetic Medicine (M.A.S., L.K.), University of Southern California School of Medicine, Los Angeles; the Department of Biochemistry and Physiology (S.B.), University of Barcelona (Spain) School of Chemistry; Laboratory of Biochemical Genetics (C.-S.U., M.P.D.), National Institutes of Health, Bethesda, Md; and the Department of Developmental Biology and Anatomy (B.P., D.S., L.T.), School of Medicine, University of South Carolina, Columbia.
Correspondence to Dr Mark A. Sussman, The Children's Hospital and Research Foundation, Division of Molecular Cardiovascular Biology, Room 3033, 3333 Burnet Ave, Cincinnati, OH 45249. E-mail sussman{at}heart.chmcc.org
Abstract—Tropomodulin is a tropomyosin-binding protein that terminates "pointed-end" actin filament polymerization. To test the hypothesis that regulation of tropomodulin:actin filament stoichiometry is critical for maintenance of actin filament length, tropomodulin levels were altered in cells by infection with recombinant adenoviral expression vectors, which produce either sense or antisense tropomodulin mRNA. Neonatal rat cardiomyocytes were infected, and sarcomeric actin filament organization was examined. Confocal microscopy indicated that overexpression of tropomodulin protein shortened actin filaments and caused myofibril degeneration. In contrast, decreased tropomodulin content resulted in the formation of abnormally long actin filament bundles. Despite changes in myofibril structure caused by altered tropomodulin expression, total protein turnover of the cardiomyocytes was unaffected. Biochemical analyses of infected cardiomyocytes indicated that changes in actin distribution, rather than altered actin content, accounted for myofibril reorganization. Ultrastructural analysis showed thin-filament disarray and revealed the presence of leptomeres after tropomodulin overexpression. Tropomodulin-mediated effects constitute a novel mechanism to control actin filaments, and our findings demonstrate that regulated tropomodulin expression is necessary to maintain stabilized actin filament structures in cardiac muscle cells.
Key Words: tropomodulin • actin • sarcomere • myofibril • cardiac, heart
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|
|
|
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|
|
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