Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure

Michael Gotthardt, Robert E. Hammer, Norbert Hübner, Jan Monti, Christian C. Witt, Mark McNabb, James A. Richardson, Henk Granzier, Siegfried Labeit, Joachim Herz

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6059-6065
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number8
DOIs
StatePublished - Feb 21 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Gotthardt, M., Hammer, R. E., Hübner, N., Monti, J., Witt, C. C., McNabb, M., Richardson, J. A., Granzier, H., Labeit, S., & Herz, J. (2003). Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure. Journal of Biological Chemistry, 278(8), 6059-6065. https://doi.org/10.1074/jbc.M211723200