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Originally published In Press as doi:10.1074/jbc.M211723200 on December 2, 2002

J. Biol. Chem., Vol. 278, Issue 8, 6059-6065, February 21, 2003
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Conditional Expression of Mutant M-line Titins Results in Cardiomyopathy with Altered Sarcomere Structure*

Michael GotthardtDagger §, Robert E. Hammer, Norbert Hübner||, Jan Monti||, Christian C. Witt**, Mark McNabbDagger Dagger , James A. Richardson§§, Henk GranzierDagger Dagger , Siegfried Labeit**, and Joachim HerzDagger ¶¶

From the Departments of Dagger  Molecular Genetics,  Biochemistry, and §§ Pathology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, || Klinische Genetik von Herz Kreislauferkrankungen, Max-Delbrück-Center for Molecular Medicine (MDC), D-13122 Berlin-Buch, Germany, the ** Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum D-68131 Mannheim, Germany, and the Dagger Dagger  Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164

Titin is a giant protein responsible for muscle elasticity and provides a scaffold for several sarcomeric proteins, including the novel titin-binding protein MURF-1, which binds near the titin M-line region. Another unique feature of titin is the presence of a serine/threonine kinase-like domain at the edge of the M-line region of the sarcomere, for which no physiological catalytic function has yet been shown. To investigate the role(s) of the titin M-line segment, we have conditionally deleted the exons MEx1 and MEx2 (encoding the kinase domain plus flanking sequences) at different stages of embryonic development. Our data demonstrate an important role for MEx1 and MEx2 in early cardiac development (embryonic lethality) as well as postnatally when disruption of M-line titin leads to muscle weakness and death at ~5 weeks of age. Myopathic changes include pale M-lines devoid of MURF-1, and gradual sarcomeric disassembly. The animal model presented here indicates a critical role for the M-line region of titin in maintaining the structural integrity of the sarcomere.

* This work was supported by grants from the Human Frontiers Science Program (to J. H. and S. L.), the Keck Foundation, the Alzheimer Association, the Perot Family Foundation, and National Institutes of Health (to M. G., H. G., and J. H.), the Deutsche Forschungsgemeinschaft (to M. G. and S. L.), and the Sofja-Kovalevskaya (to M. G.) and Wolfgang-Paul (to J. H.) programs of the Alexander von Humboldt Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address and to whom correspondence should be sent: Dept. of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Wegner Hall, Rm. 205, Pullman, WA 99164-6520. Tel.: 509-335-7784; Fax: 509-335-4650; E-mail: Gotthard@vetmed.wsu.edu.

¶¶ Established investigator of the American Heart Association.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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