Suppr超能文献

在基于肌联蛋白的信号传导受损的MDM小鼠中,CARP的诱导、肌原纤维靶向以及Nkx2.5途径的抑制。

Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling.

作者信息

Witt Christian C, Ono Yasuko, Puschmann Eva, McNabb Mark, Wu Yiming, Gotthardt Michael, Witt Stephanie H, Haak Markus, Labeit Dietmar, Gregorio Carol C, Sorimachi Hiroyuki, Granzier Henk, Labeit Siegfried

机构信息

Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim 68167, Germany.

出版信息

J Mol Biol. 2004 Feb 6;336(1):145-54. doi: 10.1016/j.jmb.2003.12.021.

Abstract

Muscular dystrophy with myositis (mdm) is a recessive mouse mutation that is caused by a small deletion in the giant elastic muscle protein titin. Homozygous mdm/mdm mice develop a progressive muscular dystrophy, leading to death at approximately 2 months of age. We surveyed the transcriptomes of skeletal muscles from 24 day old homozygous mdm/mdm and +/+ wild-type mice, an age when MDM animals have normal passive and active tensions and sarcomeric structure. Of the 12488 genes surveyed (U74 affymetrix array), 75 genes were twofold to 30-fold differentially expressed, including CARP (cardiac ankyrin repeat protein), ankrd2/Arpp (a CARP-like protein) and MLP (muscle LIM protein), all of which associate with the titin filament system. The four genes most strongly affected (eightfold to 30-fold change) were all members of the CARP-regulated Nkx-2.5-dependent signal pathway, and CARP mRNA level was 30-fold elevated in MDM skeletal muscle tissues. The CARP protein overexpressed in MDM became associated with the I-band region of the sarcomere. The mdm mutation excises the C-terminal portion of titin's N2A region, abolishing its interaction with p94/calpain-3 protease. Thus, the composition of the titin N2A protein complex is altered in MDM by incorporation of CARP and loss of p94/calpain-3. These changes were absent from the following control tissues (1). cardiac muscles from homozygous mdm/mdm animals, (2). skeletal and cardiac muscle from heterozygous mdm/+ animals, and (3). dystrophic muscles from MDX mice. Thus, the altered composition of the titin N2A complex is specific for the titin-based skeletal muscular dystrophy in MDM.

摘要

伴有肌炎的肌营养不良(mdm)是一种隐性小鼠突变,由巨大弹性肌肉蛋白肌联蛋白的小缺失引起。纯合子mdm/mdm小鼠会发展为进行性肌营养不良,大约在2月龄时死亡。我们检测了24日龄纯合子mdm/mdm小鼠和+/+野生型小鼠骨骼肌的转录组,这个年龄段的mdm动物具有正常的被动和主动张力以及肌节结构。在所检测的12488个基因(U74 Affymetrix芯片)中,有75个基因的表达差异为2倍至30倍,包括CARP(心肌锚蛋白重复蛋白)、ankrd2/Arpp(一种类似CARP的蛋白)和MLP(肌肉LIM蛋白),所有这些都与肌联蛋白丝系统相关。受影响最严重的四个基因(变化8倍至30倍)都是CARP调节的Nkx-2.5依赖性信号通路的成员,并且CARP mRNA水平在mdm骨骼肌组织中升高了30倍。在mdm中过表达的CARP蛋白与肌节的I带区域相关。mdm突变切除了肌联蛋白N2A区域的C末端部分,消除了它与p94/钙蛋白酶-3的相互作用。因此,通过CARP的掺入和p九四/钙蛋白酶-3的缺失,mdm中肌联蛋白N2A蛋白复合物的组成发生了改变。以下对照组织中不存在这些变化:(1)纯合子mdm/mdm动物的心肌,(2)杂合子mdm/+动物的骨骼肌和心肌,以及(3)MDX小鼠的营养不良肌肉。因此,肌联蛋白N2A复合物组成的改变是mdm中基于肌联蛋白的骨骼肌营养不良所特有的。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验