A-769662 activates AMPK beta1-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle.
Am J Physiol Cell Physiol
; 297(4): C1041-52, 2009 Oct.
Article
en En
| MEDLINE
| ID: mdl-19657063
ABSTRACT
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 microM (approximately 15%, P < 0.05) and 1 mM (approximately 60%, P < 0.01). AMPK beta1- but not beta2-containing complexes were dose dependently activated by A-769662 in muscles from both genotypes (approximately 100% at 200 microM 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 beta1-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pironas
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Tiofenos
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Músculo Esquelético
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Fosfatidilinositol 3-Quinasas
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Proteínas Quinasas Activadas por AMP
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Glucosa
Límite:
Animals
Idioma:
En
Revista:
Am J Physiol Cell Physiol
Asunto de la revista:
FISIOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Dinamarca