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

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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.