Role of co-chaperone, BAG3, in muscle degeneration under physiological stress

共伴侣 BAG3 在生理应激下肌肉退化中的作用

基本信息

批准号：
7825291
负责人：
SHINICHI TAKAYAMA
金额：
$ 38.11万
依托单位：
BOSTON BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-08 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7825291
关键词：
Actins Age Animals Apoptosis Apoptotic Binding Birth Caspase Cell Adhesion Cell Survival Cells Cessation of life Cytoskeletal Proteins Cytoskeleton Disease Embryo Employee Strikes Exhibits Family Fibroblasts Generations Genes Growth Heart Heat-Shock Proteins 70 Hypertrophy Inhibition of Apoptosis Knockout Mice Ligase Modeling Molecular Molecular Chaperones Mus Muscle Muscle Cells Muscle Fibers Myoblasts Myofibrils Partner in relationship Pathway interactions Peptide Hydrolases Phenotype Physiological Proteasome Inhibition Protein Binding Protein Family Proteins Proteolysis Regulation Reporting Research Personnel Respiratory Diaphragm Ring Finger Domain Role Skeletal Muscle Soleus Muscle Stress System Transgenic Mice Troponin T Ubiquitin Ubiquitination Up-Regulation human disease in vivo insight member multicatalytic endopeptidase complex muscle degeneration programs research study ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Project Summary. BAG3 is a member of co-chaperones that binds to and regulates Hsp70-family molecular chaperones. BAG3 is expressed in muscle and has been reported to possess anti-apoptotic. Mice with homozygous disruption of their bagS genes have been generated, revealing a striking post-natal phenotype whereby animals stop growing after 2 weeks of age, and uniformly die by 4 weeks. These bag3-deficient animals develop myofibrillar degeneration with apoptotic feature. The muscle degeneration is especially severe in the diaphragm and soleus muscles, suggesting that physiological use predisposes to muscle degeneration in the absence of BAG3. In bag3 deficient muscle, accumulation of ubiquitinated protein, upregulation of proteasome subunit and degradation of troponin T has been observed. Ring finger type ubiquitin ligase, Siah family protein directly interact to BAG3 protein. Additionally, several lines of evidence indicate that bagS inhibits the ubiquitin proteasome system. Gene knockdown of bag3 in C2C12 myoblast indicates increased apoptosis and accumulation of ubiquitinated proteins. Taken together, BAG3 appears to be critical for protection of muscle through inhibition of apoptosis and ubiquitin proteasome proteolysis. Experiments are proposed to explore the molecular mechanism of inhibition of apoptosis and ubiquitin proteasome including: (1) Studying the molecular mechanisms of apoptosis caused by bagS-deficiency; (2) To determine the function of BAG3 in regulation of ubiquitin proteasome and interacting protein in skeletal muscle and (3) Generation and Analyzing the effects of bag3 depletion in skeletal muscle by Cre-lox system or skeletal muscle specific over-expression of bag3 in vivo using pathophysiological model and cross mating experiments. Relevance: These studies will provide insights about the roles of BAG3 in muscle cell survival under physiological stress, and may provide us clues for understanding molecular mechanisms of myofibrillar degeneration and for investigating the new target for therapy of muscular degenerative human diseases

描述（由申请人提供）：项目摘要。 BAG3 是结合并调节 Hsp70 家族分子伴侣的共伴侣成员。 BAG3在肌肉中表达，据报道具有抗凋亡作用。 bagS 基因纯合性破坏的小鼠已经诞生，揭示了一种引人注目的产后表型，即动物在 2 周龄后停止生长，并在 4 周龄时统一死亡。这些 bag3 缺陷的动物会出现具有细胞凋亡特征的肌原纤维变性。膈肌和比目鱼肌的肌肉退化尤其严重，表明在缺乏 BAG3 的情况下，生理使用容易导致肌肉退化。在 bag3 缺陷的肌肉中，观察到泛素化蛋白的积累、蛋白酶体亚基的上调和肌钙蛋白 T 的降解。无名指型泛素连接酶、Siah家族蛋白直接与BAG3蛋白相互作用。此外，多项证据表明 bagS 抑制泛素蛋白酶体系统。 C2C12 成肌细胞中 bag3 的基因敲低表明细胞凋亡和泛素化蛋白积累增加。总而言之，BAG3 似乎通过抑制细胞凋亡和泛素蛋白酶体蛋白水解来保护肌肉。拟通过实验探索泛素蛋白酶体抑制细胞凋亡的分子机制，包括：（1）研究bagS缺陷引起细胞凋亡的分子机制； (2) 确定 BAG3 在调节骨骼肌中泛素蛋白酶体和相互作用蛋白中的功能，以及 (3) 生成并分析 Cre-lox 系统或骨骼肌中 bag3 特异性过表达对骨骼肌 bag3 缺失的影响体内使用病理生理学模型和交叉交配实验。相关性：这些研究将深入了解BAG3在生理应激下肌肉细胞存活中的作用，并可能为我们了解肌原纤维变性的分子机制和研究治疗人类肌肉退行性疾病的新靶点提供线索