Journal of Biological Chemistry
Volume 278, Issue 8, 21 February 2003, Pages 6059-6065
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MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY
Conditional Expression of Mutant M-line Titins Results in Cardiomyopathy with Altered Sarcomere Structure*

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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.

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*

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.

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Established investigator of the American Heart Association.