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Papers In Press, published online ahead of print December 2, 2002
Department of Molecular Genetics, University of Texas Southwestern, Dallas, TX 75390-9046
Corresponding Author: Joachim.Herz{at}UTSouthwestern.edu
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 titin’s 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 titin’s 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.
J. Biol. Chem, 10.1074/jbc.M211723200
Submitted on November 18, 2002
Revised on November 27, 2002
Accepted on December 2, 2002
Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure
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