title: Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+).
abstract: There is evidence suggesting that adaptive increases in GLUT4 and mitochondria in skeletal muscle occur in parallel. It has been reported that raising cytosolic Ca(2+) in myocytes induces increases in mitochondrial enzymes. In this study, we tested the hypothesis that an increase in cytosolic Ca(2+) induces an increase in GLUT4. We found that raising cytosolic Ca(2+) by exposing L6 myotubes to 5 mM caffeine for 3 h/day for 5 days induced increases in GLUT4 protein and in myocyte enhancer factor (MEF)2A and MEF2D, which are transcription factors involved in regulating GLUT4 expression. The caffeine-induced increases in GLUT4 and MEF2A and MEF2D were partially blocked by dantrolene, an inhibitor of sarcoplasmic reticulum Ca(2+) release, and completely blocked by KN93, an inhibitor of Ca(2+)-calmodulin-dependent protein kinase (CAMK). Caffeine also induced increases in MEF2A, MEF2D, and GLUT4 in rat epitrochlearis muscles incubated with caffeine in culture medium. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), which activates AMP-activated protein kinase (AMPK), also induced approximately twofold increases in GLUT4, MEF2A, and MEF2D in L6 myocytes. Our results provide evidence that increases in cytosolic Ca(2+) and activation of AMPK, both of which occur in exercising muscle, increase GLUT4 protein in myocytes and skeletal muscle. The data suggest that this effect of Ca(2+) is mediated by activation of CAMK and indicate that MEF2A and MEF2D are involved in this adaptive response.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Edward O
authors.initials: EO
authors.lastname: Ojuka
authors.forename: Terry E
authors.initials: TE
authors.lastname: Jones
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Nolte
authors.forename: May
authors.initials: M
authors.lastname: Chen
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wamhoff
authors.forename: Michael
authors.initials: M
authors.lastname: Sturek
authors.forename: John O
authors.initials: JO
authors.lastname: Holloszy
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents / Q000494:pharmacology; D064326:MEF2 Transcription Factors; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology*; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D064326:MEF2 Transcription Factors; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D012265:Ribonucleotides; C495690:Slc2a3 protein, rat; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D002110:Caffeine; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide; D002118:Calcium