Regulation of GLUT4 biogenesis in muscle: Evidence for involvement of AMPK and Ca2+

Edward O. Ojuka, Terry E. Jones, Lorraine A. Nolte, May Chen, Brian R. Wamhoff, Michael Sturek, John O. Holloszy

Research output: Contribution to journalArticle

163 Scopus citations


There is evidence suggesting that adaptive increases in GLUT4 and mitochondria in skeletal muscle occur in parallel. It has been reported that raising cytosolic Ca2+ in myocytes induces increases in mitochondrial enzymes. In this study, we tested the hypothesis that an increase in cytosolic Ca2+ induces an increase in GLUT4. We found that raising cytosolic Ca2+ 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 Ca2+ release, and completely blocked by KN93, an inhibitor of Ca2+-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 Ca2+ 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 Ca2+ is mediated by activation of CAMK and indicate that MEF2A and MEF2D are involved in this adaptive response.

Original languageEnglish (US)
Pages (from-to)E1008-E1013
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number5 45-5
StatePublished - 2002


  • 5′-adenosine monophosphate-activated protein kinase
  • Ca-calmodulin-dependent protein kinase
  • Gene expression
  • Myocyte enhancer factor 2
  • Skeletal muscle
  • Tissue culture

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Regulation of GLUT4 biogenesis in muscle: Evidence for involvement of AMPK and Ca<sup>2+</sup>'. Together they form a unique fingerprint.

  • Cite this