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

Jensen TE, Rose AJ, Hellsten Y, Wojtaszewski JF, Richter EA. Caffeine-induced Ca release increases AMPK-dependent glucose uptake in rodent soleus muscle. Am J Physiol Endocrinol Metab 293: E286–E292, 2007. First published April 3, 2007; doi:10.1152/ajpendo.00693.2006.—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 M), the CaM-competitive inhibitor KN-93 (10 M), or the SR Ca release blocking agent dantrolene (10 M) all inhibited ACC phosphorylation and 1-AMPK phosphorylation, suggesting that SR Ca 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 Ca -activated CaMKK may control 1-AMPK activation and be necessary for caffeine-stimulated glucose uptake in mouse soleus muscle.