AMPK alpha(1) Activation Is Required for Stimulation of Glucose Uptake by Twitch Contraction, but Not by H2O2, in Mouse Skeletal Muscle

作者：Jensen Thomas E^*; Schjerling Peter; Viollet Benoit; Wojtaszewski Jorgen F P; Richter Erik A

来源：PLos One, 2008, 3(5): e2102.

DOI：10.1371/journal.pone.0002102

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 alpha-AMPK isoforms, alpha(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 alpha(1) AMPK in skeletal muscle, possibly due to alpha-AMPK isoform signaling redundancy. By applying low-intensity twitch-contraction and H2O2 stimulation to activate alpha(1) AMPK, but not alpha(2) AMPK, in wildtype and alpha-AMPK transgenic mouse muscles, this study aimed to define conditions where alpha(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), alpha(1) AMPK knockout or alpha(2) AMPK knockout mice. H2O2 increased the activity of both alpha(1) and alpha(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 contrast, twitch-contraction increased the activity of alpha(1) AMPK, but not alpha(2) AMPK activity nor Akt or AS160 phosphorylation. Glucose uptake was markedly lower in alpha(1) AMPK knockout and KD AMPK muscles, but not in alpha(2) AMPK knockout muscles, following twitch stimulation.
Conclusions/Significance: These results provide strong genetic evidence that alpha(1) AMPK, but not alpha(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 alpha(1) 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.

• 出版日期2008-5-7