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RECEPTORS AND SIGNAL TRANSDUCTION

A-769662 activates AMPK β₁-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

¹Molecular Physiology Group, Copenhagen Muscle Research Centre, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark; and ²Novo Nordisk, Måløv, Denmark

Submitted 27 January 2009 ; accepted in final form 4 August 2009

5'-AMP-activated protein kinase (AMPK) regulates several aspects of metabolism. Recently, A-769662 was shown to activate AMPK in skeletal muscle. However, no biological effects of AMPK activation by A-769662 in this tissue have been reported. We hypothesized that A-769662 would increase glucose uptake in skeletal muscle. We studied incubated soleus and extensor digitorum longus (EDL) muscles from 129S6/sv and C57BL/6 mice. Glucose uptake increased only in soleus from 129S6/sv when concentrations of A-769662 were 500 µM (15%, P < 0.05) and 1 mM (60%, P < 0.01). AMPK β₁- but not β₂-containing complexes were dose dependently activated by A-769662 in muscles from both genotypes (100% at 200 µM and 300–600% at 1 mM). The discrepancy between the A-769662-induced AMPK activation pattern and stimulation of glucose uptake suggested that these effects were unrelated. A-769662 increased phosphorylation of Akt in both muscles from both genotypes, with phosphorylation of T308 being significantly higher in soleus than in EDL in 129S6/sv mice (P < 0.01). In soleus from 129S6/sv mice, insulin receptor substrate 1-associated phosphatidylinositol 3 (PI3)-kinase activity was markedly increased with A-769662, and Akt phosphorylation and glucose uptake were inhibited by wortmannin while phosphorylation of acetyl-CoA carboxylase (S227) was unaffected. Thus, A-769662 activates β₁-containing AMPK complexes in skeletal muscle but induces glucose uptake through a PI3-kinase-dependent pathway. Although development of A-769662 has constituted a step forward in the search for AMPK activators targeting specific AMPK trimers, our data suggest that in intact muscle, A-769662 has off-target effects. This may limit use of A-769662 to study the role of AMPK in skeletal muscle metabolism.

a-769662; phosphatidylinositol 3-kinase; adenosine 5'-monophosphate-activated protein kinase trimer composition; extensor digitorum longus; soleus; C57BL/6; 129S6/sv; TBC1D1; TBC1D4