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

肌肉收缩伴随着细胞和组织的被动拉伸或变形。本研究旨在阐明被动牵张条件下小鼠骨骼肌葡萄糖转运蛋白4（GLUT 4）转位和葡萄糖摄取的分子机制。获得了以下结果：1.被动牵拉主要诱导GLUT 4从细胞内膜向质膜移位，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均诱导GLUT 4从细胞内膜向质膜和横小管移位，沿着葡萄糖摄取.机械牵张增加了蛋白激酶B（Akt）和p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化，但对代谢传感分子AMP活化蛋白激酶（AMPK）的活性无明显影响.另一方面，电刺激不仅增强AMPK的活性，而且增强Akt和p38 MAPK的磷酸化。建立了小鼠腓肠肌微束制备方法，为进一步阐明其分子机制奠定了基础.结果表明，机械牵张可使磷脂酰肌醇激酶（PI 3 K）从胞浆转位到质膜小窝附近的小窝蛋白3（caveolin-3），并以非AMPK和胰岛素依赖的方式激活PI 3 K-Akt通路，导致GLUT 4转位和葡萄糖摄取。这意味着被动拉伸可以在没有胰岛素的情况下激活胰岛素介导的细胞内信号传导。此外，该研究表明了伴随运动的葡萄糖摄取的新分子机制，这将促进用于调节健康和疾病中的葡萄糖代谢的新策略/药物的开发。

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.