Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase

Skeletal muscle GLUT-4 transcription in response to treatment with 5-aminoi midazole-4-carboxamide-1-beta -D-ribofuranoside (AICAR), a known activator of AMP-activated protein kinase (AMPK), was studied in rats and mice. The i ncrease in GLUT-4 mRNA levels in response to a single subcutaneous injectio n of AICAR, peaked at 13 h in white and red quadriceps muscles but not in t he soleus muscle. The mRNA level of chloramphenicol acyltransferase reporte r gene which is driven by 1,154 or 895 bp of the human GLUT-4 proximal prom oter was increased in AICAR-treated transgenic mice, demonstrating the tran scriptional upregulation of the GLUT-4 gene by AICAR. However, this inducti on of transcription was not apparent with 730 bp of the promoter. In additi on, nuclear extracts from AICAR-treated mice bound to the consensus sequenc e of myocyte enhancer factor-2 (from -473 to -464) to a greater extent than from saline-injected mice. Thus AMP-activated protein kinase activation by AICAR increases GLUT-4 transcription by a mechanism that requires response elements within 895 bp of human GLUT-4 proximal promoter and that may be c ooperatively mediated by myocyte enhancer factor-2.