Caffeine-induced Ca2+ release increases AMPK-dependent glucose uptake in rodent soleus muscle

Thomas E. Jensen, Adam J. Rose, Ylva Hellsten, Jørgen F P Wojtaszewski, Erik A. Richter

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Previous studies have proposed that caffeine-induced activation of glucose transport in skeletal muscle is independent of AMP-activated protein kinase (AMPK) because α-AMPK Thr172 phosphorylation was not increased by caffeine. However, our previous studies, as well as the present, show that AMPK phosphorylation measured in whole muscle lysate is not a good indicator of AMPK activation in rodent skeletal muscle. In lysates from incubated rat soleus muscle, a predominant model in previous caffeine-studies, both acetyl-CoA carboxylase-β (ACCβ) Ser221 and immunoprecipitated α1-AMPK activity increased with caffeine incubation, without changes in AMPK phosphorylation or immunoprecipitated α2-AMPK activity. This pattern was also observed in mouse soleus muscle, where only ACCβ and α1-AMPK phosphorylation were increased following caffeine treatment. Preincubation with the selective CaMKK inhibitor STO-609 (5 μM), the CaM-competitive inhibitor KN-93 (10 μM), or the SR Ca 2+ release blocking agent dantrolene (10 μM) all inhibited ACCβ phosphorylation and α1-AMPK phosphorylation, suggesting that SR Ca2+ release may work through a CaMKK-AMPK pathway. Caffeine-stimulated 2-deoxyglucose (2DG) uptake reflected the AMPK activation pattern, being increased with caffeine and inhibited by STO-609, KN-93, or dantrolene. The inhibition of 2DG uptake is likely causally linked to AMPK activation, since muscle-specific expression of a kinase-dead AMPK construct greatly reduced caffeine-stimulated 2DG uptake in mouse soleus. We conclude that a SR Ca2+-activated CaMKK may control α1-AMPK activation and be necessary for caffeine-stimulated glucose uptake in mouse soleus muscle.

Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number1
Publication statusPublished - Jul 2007
Externally publishedYes


  • Adenosine 5′-monophosphate-activated protein kinase
  • Calcium/calmodulin kinase kinase
  • Dantrolene
  • KN-93
  • STO-609

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