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Background  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, α 2  AMPK is clearly required for stimulation of glucose transport into muscle by certain stimuli. In contrast, no clear function has yet been determined for α 1  AMPK in skeletal muscle, possibly due to α-AMPK isoform signaling redundancy. By applying low-intensity twitch-contraction and H 2 O 2  stimulation to activate α 1  AMPK, but not α 2  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 H 2 O 2  (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), α 1  AMPK knockout or α 2  AMPK knockout mice. H 2 O 2  increased the activity of both α 1  and α 2  AMPK in addition to Akt phosphorylation, and H 2 O 2 -stimulated glucose uptake was not reduced in any of the AMPK transgenic mouse models compared with wild type. In contrast, twitch-contraction increased the activity of α 1  AMPK, but not α 2  AMPK activity nor Akt or AS160 phosphorylation. Glucose uptake was markedly lower in α 1  AMPK knockout and KD AMPK muscles, but not in α 2  AMPK knockout muscles, following twitch stimulation.    Conclusions/Significance  These results provide strong genetic evidence that α 1  AMPK, but not α 2  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 α 1  AMPK in regulating a physiological endpoint in skeletal muscle. In contrast, AMPK is not essential for H 2 O 2 -stimulated muscle glucose uptake, as proposed by recent studies.

AMPK α1 Activation Is Required for Stimulation of Glucose Uptake by Twitch Contraction, but Not by H2O2, in Mouse Skeletal Muscle