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

Department of Exercise and Sport Sciences, Copenhagen Muscle Research Center, Section of Human Physiology, University of Copenhagen, Copenhagen, Denmark

Submitted 19 December 2006 ; accepted in final form 19 March 2007

Previous studies have proposed that caffeine-induced activation of glucose transport in skeletal muscle is independent of AMP-activated protein kinase (AMPK) because -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- (ACC) Ser221 and immunoprecipitated ₁-AMPK activity increased with caffeine incubation, without changes in AMPK phosphorylation or immunoprecipitated ₂-AMPK activity. This pattern was also observed in mouse soleus muscle, where only ACC and ₁-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 Ca²⁺ release blocking agent dantrolene (10 µM) all inhibited ACC phosphorylation and ₁-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 ₁-AMPK activation and be necessary for caffeine-stimulated glucose uptake in mouse soleus muscle.

adenosine 5'-monophosphate-activated protein kinase; STO-609; KN-93; dantrolene; calcium/calmodulin kinase kinase

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