Knockout of the α2 but Not α1, 5′-AMP-activated Protein Kinase Isoform Abolishes 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside- but Not Contraction-induced Glucose Uptake in Skeletal Muscle

Abstract

We investigated the importance of the two catalytic α-isoforms of the 5′-AMP-activated protein kinase (AMPK) in 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and contraction-induced glucose uptake in skeletal muscle. Incubated soleus and EDL muscle from whole-body α2 or α1-AMPK knockout (KO) and wild type (WT) mice were incubated with 2.0 mM AICAR or electrically stimulated to contraction. Both AICAR and contraction increased 2DG uptake in WT muscles. KO of α2 but not α1, abolished AICAR-induced glucose uptake, whereas neither KO affected contraction-induced glucose uptake. AICAR and contraction increased α2- and α1-AMPK activity in wild type (WT) muscles. During AICAR stimulation, the remaining AMPK activity in KO muscles increased to the same level as in WT. During contraction, the remaining AMPK activity in α 2-KO muscles was elevated by 100% probably explained by a 2-3-fold increase in α1-protein. In α1-KO muscles, α2-AMPK activity increased to similar levels as in WT. Both interventions increased total AMPK activity, as expressed by AMPK-P and ACCβ, in WT muscles. During AICAR stimulation, this was dramatically reduced in α2-KO but not in α1-KO, whereas during contraction, both measurements were essentially similar to WT in both KO-muscles. The results show that α2-AMPK is the main donor of basal and AICAR-stimulated AMPK activity and is responsible for AICAR-induced glucose uptake. In contrast, during contraction, the two α-isoforms seem to substitute for each other in terms of activity, which may explain the normal glucose uptake despite the lack of either α2 or α 1-AMPK. Alternatively, neither α-isoform of AMPK is involved in contraction-induced muscle glucose uptake.