Abstract

We investigated the importance of the two catalytic alpha-isoforms of the 5'-AMP-activated protein kinase (AMPK) in 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) and contraction-induced glucose uptake in skeletal muscle. Incubated soleus and EDL muscle from whole-body alpha2- or alpha1-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 alpha2, but not alpha1, abolished AICAR-induced glucose uptake, whereas neither KO affected contraction-induced glucose uptake. AICAR and contraction increased alpha2- and alpha1-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 alpha2-KO muscles was elevated by 100% probably explained by a 2-3-fold increase in alpha1-protein. In alpha1-KO muscles, alpha2-AMPK activity increased to similar levels as in WT. Both interventions increased total AMPK activity, as expressed by AMPK-P and ACCbeta-P, in WT muscles. During AICAR stimulation, this was dramatically reduced in alpha2-KO but not in alpha1-KO, whereas during contraction, both measurements were essentially similar to WT in both KO-muscles. The results show that alpha2-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 alpha-isoforms seem to substitute for each other in terms of activity, which may explain the normal glucose uptake despite the lack of either alpha2- or alpha1-AMPK. Alternatively, neither alpha-isoform of AMPK is involved in contraction-induced muscle glucose uptake.

Highlights

  • We investigated the importance of the two catalytic ␣-isoforms of the 5؅-AMP-activated protein kinase (AMPK) in 5-aminoimidazole-4-carboxamide-1-␤-4-ribofuranoside (AICAR) and contraction-induced glucose uptake in skeletal muscle

  • We have shown that knockout of the ␣2-isoform of AMPK completely abolished AICAR-induced glucose uptake in mouse skeletal muscle, whereas knockout of the ␣1-isoform had no effect in this respect

  • The ␣2-isoform delivered the vast majority of total AMPK activity in the basal state and during AICAR stimulation

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Summary

Introduction

We investigated the importance of the two catalytic ␣-isoforms of the 5؅-AMP-activated protein kinase (AMPK) in 5-aminoimidazole-4-carboxamide-1-␤-4-ribofuranoside (AICAR) and contraction-induced glucose uptake in skeletal muscle. Activation of AMPK initiates a complex series of signaling events, causing an increase in uptake and oxidation of substrates for ATP synthesis concurrent with decreasing ATP consuming biosynthetic processes such as protein [3, 4], lipid [1], and glycogen synthesis [5, 6] Both human and rodent studies have shown that AMPK in skeletal muscle is activated during exercise in vivo [7,8,9,10] and during contraction in vitro [11,12,13,14,15] probably by several coinciding mechanisms.

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