application): Muscle GLUT4 plays an important role in maintaining glucose homeostasis and relatively small increases of GLUT4 protein lead to substantial changes in glucose disposal. Thus, the GLUT4 gene is a rational target for intervention for the treatment of NIDDM. At present exercise is the only means available for increasing expression of the GLUT4 gene. Exercise increases the transcription rate of the GLUT4 gene, but the increase in GLUT4 protein is even greater than can be accounted for by the increase in GLUT4 mRNA. Thus, it is believed that exercise increases both the transcription and translation rates of GLUT4 to increase glucose transport in muscle and improve glucose tolerance. In this grant application the investigators propose experiments to investigate the mechanism that bring about the increase in GLUT4 glucose transport protein in response to exercise. To explain the increased rate of transcription after exercise our hypothesis that muscle contraction """"""""activates"""""""" a transcription factor that binds to an """"""""exercise response element (ERE)"""""""" in the GLUT4 promoter and activates transcription of the GLUT4 gene. To investigate this hypothesis they will establish the region of the GLUT4 gene that contains the exercise response element (ERE), determine the DNA sequence of the ERE and then use that sequence to isolate and characterize the transcription factor that is activated by exercise. Since the increase in GLUT4 protein in response to exercise training is greater than the increase in GLUT4 mRNA, it seems likely that there is an additional adaptation to exercise at the level of either translation of the message or in the degradation of GLUT4 protein. It has been established that there are two splice variants of the GLUT4 mRNA and our hypothesis is that exercise selectively increases the GLUT4 splice variant which is more readily translated. This will be investigated by measuring the rates of translation and the muscle levels of the two splice variants of GLUT4 mRNA in control and exercised trained rat muscle.
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