AMPK α(1) Activation Is Required for Stimulation of Glucose Uptake by Twitch Contraction, but Not by H(2)O(2), in Mouse Skeletal Muscle

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.