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

被引:114
作者
Gotthardt, M
Hammer, RE
Hübner, N
Monti, J
Witt, CC
McNabb, M
Richardson, JA
Granzier, H
Labeit, S
Herz, J
机构
[1] Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Pullman, WA 99164 USA
[2] Univ Texas, SW Med Ctr, Dept Mol Genet, Dallas, TX 75390 USA
[3] Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA
[4] Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA
[5] Max Delbruck Ctr Mol Med, Klin Genet Herz Kreislauferkrankungen, D-13122 Berlin, Germany
[6] Univ Klinikum, Inst Anasthesiol & Operat Intens Med, D-68131 Mannheim, Germany
关键词
D O I
10.1074/jbc.M211723200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Ranking 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 similar to5 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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收藏
页码:6059 / 6065
页数:7
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