In previously funded research we discovered that exercise training increases muscle GLUT4 protein approximately 2-3 fold and this change is accompanied by greater insulin sensitivity in human subjects and increased muscle glucose transport rates in experimental animals. We recently discovered that treating mice with AICAR (an activator of muscle AMP-kinase) also causes GLUT4 gene transcription to be increased. To understand how GLUT4 gene expression is regulated we propose investigating transcription in physiological situations where GLUT4 is differentially expressed. GLUT4 protein is higher in red muscle than white muscle, is increased by exercise and is decreased by denervation. The evidence that the transcription factor MEF2 is important in regulation of GLUT4 gene expression is very strong. Thus, it is possible that MEF2 is more active (binds to the GLUT4 promoter to turn on transcription) in red muscle fibers and in exercised muscle. Since energy charge (ATP/AMP) and calcium concentrations are changed in exercising muscle, we believe that these are good signal candidates. Thus, we plan to test the role of AMP-activated kinase (AMPK), calcium/calmodulin-activated kinase (CaM kinase) and calcineurin (a calcium/calmodulin-activated phosphatase) in modulating MEF2 in muscle to increase GLUT4 transcription in red muscle fibers and exercising muscle and decrease GLUT4 expression in denervated muscle. Transgenic animals that express inactive AMPK, activated CaM kinase, and activated calcineurin will be used to study the mechanism of regulation of GLUT4 gene transcription. These studies will provide important general information about mechanisms of adaptation to exercise. There are a large number of genes that are regulated in response to exercise and finding the transcription factor(s) that regulates GLUT4 will provide information that may be important to other adaptive mechanisms. Thus, we feel that the proposed mechanistic studies will provide information that will improve health care for diabetics and increase our knowledge about how the muscle adapts to exercise.
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