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

Abstract

EA. Caffeine-induced Ca 2ϩ 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 2ϩ release blocking agent dantrolene (10 M) all inhibited ACC␤ phosphorylation and ␣ 1-AMPK phosphorylation, suggesting that SR Ca 2ϩ 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 2ϩ -activated CaMKK may control ␣1-AMPK activation and be necessary for caffeine-stimulated glucose uptake in mouse soleus muscle. adenosine 5Ј-monophosphate-activated protein kinase; STO-609; KN-93; dantrolene; calcium/calmodulin kinase kinase SARCOPLASMIC RETICULUM (SR) Ca 2ϩ release, a prerequisite for skeletal muscle contraction, may signal to increase skeletal muscle glucose uptake (8, 21). Although cell culture-based studies have suggested the involvement of conventional PKC isoforms, but not AMP-activated protein kinase (AMPK) or CaMKII in this process in L6 myotubes devoid of sarcomeres (15,29), recent studies in incubated mature rat skeletal muscle have proposed a model in which two parallel signaling pathways, defined by CaMKII and AMPK, are necessary and sufficient to account for the entire contraction-stimulated increase in glucose uptake (32,33). In those studies, the authors have suggested that CaMKII and AMPK each account for approximately one-half of the contraction increase in glucose uptake in glycolytic rat epitroclearis, whereas CaMKII accounts for all of the contraction increase in oxidative rat soleus muscle. A crucial control in these studies was that stimulation of SR Ca 2ϩ release below the contraction threshold by caffeine increases glucose uptake with...

AMPKα2deficiency uncovers time dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle

“…Although glucose uptake was lower with caffeine treatment in the DN mice, there continued to be elevated glucose uptake rates over resting conditions. This increase in glucose uptake supports the notion that glucose uptake is regulated by Ca 2ϩ signaling intermediates that are independent of AMPK activation (22,53). Our results further suggest that AMPK␣ 2 activation may be more critical to the regulation of glucose metabolism during states of increased intracellular [Ca 2ϩ ] induced by caffeine than to the regulation of FA metabolism in skeletal muscle.…”

“…It has been shown by us and others that caffeine-induced increases in Ca 2ϩ signaling regulate substrate metabolism, possibly via AMPK activation (1,6,22,35). Indeed, we have shown that when CaMKII or CaMKK was inhibited during caffeine stimulation, there were subsequent decreases in AMPK␣ 2 activity along with decreases in the rates of FA uptake, glucose uptake, and FA oxidation (1,35).…”

High Rates Of Muscle Glycogen Resynthesis After Exhaustive Exercise When Carbohydrate Is Co-ingested With Caffeine

“…While our results do not support a role for AMPK in caffeine-induced glucose transport, Jensen et al (20) recently reported that AMPK is causally linked to the caffeinestimulated glucose uptake response. These workers provide evidence to demonstrate that caffeine exerts an isoform-specific increase in AMPK ␣ 1 activity and acetyl-CoA carboxylase (ACC)␤ phosphorylation in the absence of total AMPK Thr172 phosphorylation (20). Accordingly, they propose that investigations that have only measured total AMPK Thr172 phosphorylation may be prone to type 2 errors and have resulted in false conclusions with regard to the effect of caffeine on AMPK activation.…”

A histological and immunohistochemical study of beta cells in streptozotocin diabetic rats treated with caffeine

“…However, supplementation of the diet with cocoa powder extract has been suggested to reduce blood glucose concentration in STZ-induced diabetes in rats [24]. Caffeine is known to increase the glucose transport rate in the absence of insulin in rodent skeletal muscles [25,26]. Also, caffeine activates cyclic AMP-dependent protein kinase through an insulin-independent mechanism, which increases AMP kinase-1 to promote glucose transport.…”