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Am J Physiol Endocrinol Metab 289: E1071-E1076, 2005. First published August 16, 2005; doi:10.1152/ajpendo.00606.2004
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Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase

Burton F. Holmes,1,2 David P. Sparling,2 Ann Louise Olson,3 William W. Winder,4 and G. Lynis Dohm2

1Department of Exercise and Sport Science, Human Performance Laboratory and 2Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina; 3Department of Biochemistry, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and 4Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah

Submitted 22 December 2004 ; accepted in final form 19 May 2005

As the primary glucose transporter in skeletal muscle, GLUT4 is an important factor in the regulation of blood glucose. We previously reported that stimulation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside (AICAR) increased GLUT4 expression in muscle. GLUT4 enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2) have been shown to be important for normal GLUT4 expression because deletion or truncation of the consensus sequences on the promoter causes depressed GLUT4 mRNA expression. This led to the current study to investigate possible roles for GEF and MEF2 in mediating the activation of GLUT4 gene transcription in response to AMPK. Here we show that, although AMPK does not appear to phosphorylate MEF2A, AMPK directly phosphorylates the GEF protein in vitro. MEF2 and GEF are activated in response to AMPK as we observed translocation of both to the nucleus after AICAR treatment. Nuclear MEF2 protein content was increased after 2 h, and GEF protein was increased in the nucleus 1 and 2 h post-AICAR treatment. Last, GEF and MEF2 increase in binding to the GLUT4 promoter within 2 h after AICAR treatment. Thus we conclude that GEF and MEF2 mediate the AMPK-induced increase in transcription of skeletal muscle GLUT4. AMPK can phosphorylate GEF and in response to AICAR, GEF, and MEF2 translocate to the nucleus and have increased binding to the GLUT4 promoter.

5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside; glutathione S-transferase; glucose transporter 4



Address for reprint requests and other correspondence: B. F. Holmes, Dept. of Biochemistry and Molecular Physics, Univ. of Arizona, Tucson, AZ 85721 (e-mail: bfh0530{at}arizona.edu)




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