Molecular mechanisms for regulation of glucose metabolism in skeletal muscle cells by biomechanical stress.

通过生物力学应激调节骨骼肌细胞葡萄糖代谢的分子机制。

基本信息

批准号：
18590064
负责人：
NAKAYAMA Koichi
金额：
$ 2.55万
依托单位：
Iwate Medical University (2007)University of Shizuoka (2006)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Muscle contraction is accompanied by passive stretching or deformation of cells and tissues. The present research project aimed to clarify molecular mechanisms involved in glucose transporter 4 (GLUT4) translocation and glucose uptake in skeletal muscles of mice in response to passive stretching. The following results were obtained :1. Passive stretching mainly induced GLUT4 translocation from an intracellular membrane to a plasma membrane and accelerated glucose uptake in hindlimb muscles, whereas electrical stimulation, which mimics physical exercise in vivo, and insulin each induced GLUT4 translocation from an intracellular membrane to plasma membrane and to transverse tubules, along with subsequent glucose uptake.2. Mechanical stretching increased phosphorylation of protein kinase B (Akt) and p38 mitogen-activated protein kinase (p38 MAPK), but it had no apparent effect on the activity of AMP-activated protein kinase (AMPK), a metabolic sensor molecule.3. Electrical stimulation, on the other hand, augmented the activity of not only AMPK but also phosphorylation of Akt and p38 MAPK.4. We established a preparation of micro bundles of gastrocnemius muscle in mice for further elucidation of molecular mechanisms.5. Mechanical stretching translocated phosphatidylinositol kinase (PI3K) from cytosol to caveolin-3 near caveolae of plasma membrane when assessed by immunostaining assay and confocal laser microscopy.The results suggest that passive stretching activates PI3K-Akt pathway in AMPK- and insulin-independent manners, which produces translocation of GLUT4 and the glucose uptake. This means that passive stretching could alternatively activate intracellular signalings mediated by insulin without insulin. Furthermore, the study indicates a new molecular mechanism for glucose uptake accompanied with exercise, which will promote the development of a novel strategy/drug for regulation of glucose metabolism in health and disease.

肌肉收缩伴随着细胞和组织的被动拉伸或变形。本研究项目旨在阐明小鼠骨骼肌被动拉伸时葡萄糖转运蛋白 4 (GLUT4) 易位和葡萄糖摄取的分子机制。得到如下结果： 1．被动拉伸主要诱导GLUT4从细胞内膜易位到质膜，并加速后肢肌肉的葡萄糖摄取，而模拟体内体育锻炼的电刺激和胰岛素分别诱导GLUT4从细胞内膜易位到质膜和横小管，以及随后的葡萄糖摄取。2。机械拉伸增加了蛋白激酶B（Akt）和p38丝裂原激活蛋白激酶（p38 MAPK）的磷酸化，但对代谢传感器分子AMP激活蛋白激酶（AMPK）的活性没有明显影响。3．另一方面，电刺激不仅增强了 AMPK 的活性，还增强了 Akt 和 p38 MAPK.4 的磷酸化。我们建立了小鼠腓肠肌微束的制备方法，以进一步阐明其分子机制。 5．通过免疫染色测定和共焦激光显微镜评估，机械拉伸将磷脂酰肌醇激酶 (PI3K) 从胞质溶胶转移到质膜小窝附近的 Caveolin-3。结果表明，被动拉伸以 AMPK 和胰岛素独立的方式激活 PI3K-Akt 通路，这产生 GLUT4 的易位和葡萄糖摄取。这意味着被动拉伸可以在没有胰岛素的情况下激活由胰岛素介导的细胞内信号传导。此外，该研究表明了运动伴随的葡萄糖摄取的新分子机制，这将促进开发调节健康和疾病中葡萄糖代谢的新策略/药物。