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(Circulation Research. 2006;99:323.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Cardiac Myosin Light Chain-2

A Novel Essential Component of Thick-Myofilament Assembly and Contractility of the Heart

Wolfgang Rottbauer, Georgia Wessels, Tillman Dahme, Steffen Just, Nicole Trano, David Hassel, Charles Geoffrey Burns, Hugo A. Katus, Mark C. Fishman

From the Department of Medicine III (W.R., G.W., T.D., S.J., N.T., D.H., H.A.K.), University of Heidelberg, Germany; Cardiovascular Research Center (W.R., C.G.B., M.C.F.), Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Boston, Mass; and Novartis Institutes for BioMedical Research (M.C.F.), Cambridge, Mass.

Correspondence to W. Rottbauer, Department of Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany. E-mail wolfgang.rottbauer{at}med.uni-heidelberg.de

Although it is well known that mutations in the cardiac regulatory myosin light chain-2 (mlc-2) gene cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of MLC-2 in the heart are only poorly understood. We have isolated a mutation in zebrafish, tell tale heart (tel^m225), which selectively perturbs contractility of the embryonic heart. By positional cloning, we identified tel to encode the zebrafish mlc-2 gene. In contrast to mammals, zebrafish have only 1 cardiac-specific mlc-2 gene, which we find to be expressed in atrial and ventricular cardiomyocytes during early embryonic development, but also in the adult heart. Accordingly, loss of zMLC-2 function cannot be compensated for by upregulation of another mlc-2 gene. Surprisingly, ultrastructural analysis of tel cardiomyocytes reveals complete absence of organized thick myofilaments. Thus, our findings provide the first in vivo evidence that cardiac MLC-2 is required for thick-filament stabilization and contractility in the vertebrate heart.

Key Words: cardiac myosin light chain-2 • myofibrillogenesis • zebrafish heart

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