Molecular mechanism of unloading-mediated insulin resistance

卸载介导的胰岛素抵抗的分子机制

• 批准号: 15500449
• 负责人: NIKAWA Takeshi
• 金额: $ 2.43万
• 依托单位: The University of Tokuahima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15500449/
• 关键词: Cbl-b; unloading; ubiquitin-ligase; spaceflight; tail-suspension; insulin resistance; muscle atrophy; ユビチキンリガーゼ; インスリン; インスリン様増殖因子; Unloading

Skeletal muscle unloading during prolonged bed rest, paralysis, or spaceflight can result in debilitating skeletal muscle atrophy. Reduced muscle mass is characterized by a combination of decreased protein synthesis and increased protein degradation. Currently, there is no treatment to reverse the progression of atrophy. Here we show that Cbl-b, a RING-type member of the ubiquitin ligase family, is essential for skeletal muscle atrophy. Expression of Cbl-b in vivo induces significant atrophy in rat tibialis anterior muscle. In contrast, Cbl-b deficient mice are resistant to muscle atrophy and dysfunction induced during unloading by tail suspension. Upon tail suspension or zero gravity, Cbl-b interacts with and thereby degrades the skeletal muscle growth factor signaling intermediate IRS-1. Thus, Cbl-b activation appears to underlie the refractoriness of atrophic muscle tissue to growth factor stimulation by IGF/insulin and likely accounts for the overall decrease in protein synthesis observed during muscle wasting. These data suggest that Cbl-b may be a novel target for the development of therapeutics aimed at the preservation of muscle mass and function during a variety of muscle wasting diseases.

在长时间的床休息，瘫痪或太空飞行过程中，骨骼肌卸载会导致骨骼肌萎缩。减少的肌肉质量的特征是蛋白质合成降低和蛋白质降解增加的结合。当前，尚无治疗方法来扭转萎缩的进展。在这里，我们表明CBL-B是泛素连接酶家族的环形型成员，对于骨骼肌萎缩至关重要。 CBL-B在体内的表达会诱导大鼠胫骨前肌的显着萎缩。相比之下，CBL-B缺乏小鼠对通过尾悬浮液卸载期间引起的肌肉萎缩和功能障碍具有抗性。在尾悬浮或零重力时，CBL-B与骨骼肌肉生长因子信号传导中间IRS-1相互作用。因此，CBL-B激活似乎是IGF/胰岛素对生长因子刺激的萎缩性的基础，并可能解释了肌肉浪费期间观察到的蛋白质合成的总体下降。这些数据表明，CBL-B可能是开发旨在在各种肌肉浪费疾病期间保存肌肉质量和功能的治疗剂的新目标。

项目成果

Moderate hypergravity does not affect protein-ubiquitination and proliferation of rat L6 myoblastic cells.

中度超重力不影响大鼠 L6 成肌细胞的蛋白质泛素化和增殖。

• 发表时间: 2005
• 期刊: Biol.Sci.Space (in press)
• 作者: Hirasaka K. et al.;Hirasaka K.et al.
• 通讯作者: Hirasaka K.et al.

Osteoactivin up-regulates expression of MMPs-3 and 9 in fibroblasts infiltrated into denervated skeletal muscle in mice.

骨激活素上调小鼠去神经骨骼肌中浸润的成纤维细胞中 MMP-3 和 9 的表达。

• 发表时间: 2005
• 期刊: Am.J.Physiol. (in press)
• 作者: Hirasaka K. et al.;Hirasaka K.et al.;Ogawa T.et al.
• 通讯作者: Ogawa T.et al.

Clinorotation prevents differentiation of rat myoblastic cells in association with reduced NF-κB-Signaling.

旋转可防止与 NF-κB 信号传导减弱相关的大鼠成肌细胞分化。

• 发表时间: 2005
• 期刊: Biochim.Biophys.Acta 1743(1-2)
• 作者: Hirasaka K. et al.

Sakamaki T.et al.: "The pathogenesis of slippage and deformity in pediatric lumbar spine. A radiographic and histological study using a new rat in vivo model"Spine. 28. 645-651 (2003)

Sakamaki T.等人：“小儿腰椎滑移和畸形的发病机制。使用新的大鼠体内模型进行放射学和组织学研究”脊柱。

Physical stress by magnetic force accelerates differentiation of humman osteoblasts.

磁力造成的物理压力加速人类成骨细胞的分化。

• 发表时间: 2003
• 期刊: Biochem.Biophys.Res.Commun. 311(1)
• 作者: Hirasaka K. et al.;Hirasaka K.et al.;Ogawa T.et al.;Ogawa T.et al.;Hirasaka K.et al.;Mishiro T. et al.;Nikawa T. et al.;Mishiro T.et al.;Nikawa T.et al.;Yuge L.et al.
• 通讯作者: Yuge L.et al.