AMPK α1 activation is required for stimulation of glucose uptake by twitch contraction, but not by H2O2, in mouse skeletal muscle

Abstract

Bakground: AMPK is a promising pharmacological target in relation to metabolic disorders partly due to its non-insulin dependent glucose uptake promoting role in skeletal muscle. Of the 2 catalytic α-AMPK isoforms, α2 AMPK is clearly required for stimulation of glucose transport into muscle by certain stimuli. In contrast no clear functions has yet been determined for α1 AMPK in skeletal muscle, possibly due to α-AMPK isoform signaling redundancy. By applying low-intensity twitch-contraction and H2O2 stimulation to activate α, AMPK, but not α2 AMPK, in wildtype and α-AMPK transgenic mouse muscles, this study aimed to define conditions where α 1 AMPK is required to increase muscle glucose uptake. Methodology/Principal Findings: Following stimulation with H2O2 (3 mM, 20 min) or twitch-contraction (0.1 ms pulse, 2 Hz, 2 min), signaling and 2-deoxyglucose uptake were measured in incubated soleus muscles from wildtype and muscle-specific kinase-dead AMPK (KD), α1 AMPK knockout or α 2 AMPK knockout mice. H2O2 increased the activity of both α1 and α 2 AMPK in addition to Akt phosphorylation and H2O2-stimulated glucose uptake was not reduced in any of the AMPK transgenic mouse models compared with wild type. In contrst, twitch-contraction increased the activity of α 1 AMPK, but not α2 AMPK activity nor Akt or AS160 phosphorylation. Glucose uptake was markedly lower in α1 AMPK knockout and KD AMPK muscles, but not in α2 AMPK knockout muscles, following twitch stimulation. Conclusions/Significance: These results provide strong genetic evidencet that α1 AMPK, but not α2 AMPK, Akt or AS160, is necessary for regulation of twitch-contraction stimulated glucose uptake. To our knowledge, this is the first report to show a major and essential role of α1 AMPK in regulating a physiological endpoint in skeletal muscle. In contrast, AMPK is not essential for H2O2-stimulated muscle glucose uptake, as proposed by recent studies. © 2008 Jensen et al.