Abstract
BackgroundAMPK 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 function 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 α1 AMPK, but not α2 AMPK, in wildtype and α-AMPK transgenic mouse muscles, this study aimed to define conditions where α1 AMPK is required to increase muscle glucose uptake.Methodology/Principal FindingsFollowing 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 α2 AMPK knockout mice. H2O2 increased the activity of both α1 and α2 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 α1 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/SignificanceThese results provide strong genetic evidence 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.
Highlights
AMP activated protein kinase (AMPK) is emerging as an attractive target in both prophylaxis and treatment of metabolic disorders, including obesity and type 2 diabetes[1]
H2O2 stimulation of glucose uptake did not differ between wild type and either a1 AMPK knockout muscle (KO) (Figure 2E) or KD AMPK muscles (Figure 2F)
These results show that H2O2 stimulation of glucose uptake in muscle does not require AMPK catalytic activity and activates at least one other candidate glucose uptake promoting protein
Summary
AMP activated protein kinase (AMPK) is emerging as an attractive target in both prophylaxis and treatment of metabolic disorders, including obesity and type 2 diabetes[1]. Using AMPK signaling-deficient transgenic mouse models, various research groups have demonstrated that the skeletal muscle enriched catalytic a2 AMPK isoform is necessary to increase glucose uptake into skeletal muscle with certain stimuli, including 5aminoimidazole-4-carboxamide ribonucleoside (AICAR), hypoxia and metabolic uncoupling[2,3,4]. Both a2 AMPK and Akt signaling phosphorylate the Rab-GAP protein AS160, a probable regulator of GLUT4 translocation during contraction and insulin-stimulation[5,6]. By applying lowintensity twitch-contraction and H2O2 stimulation to activate a1 AMPK, but not a2 AMPK, in wildtype and a-AMPK transgenic mouse muscles, this study aimed to define conditions where a1 AMPK is required to increase muscle glucose uptake
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