AMPK alpha1 activation is required for stimulation of glucose uptake by twitch contraction, but not by H2O2, in mouse skeletal muscle.
AMPK alpha1 activation is required for stimulation of glucose uptake by twitch contraction, but not by H2O2, in mouse skeletal muscle.
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DOI：
10.1371/journal.pone.0002102
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发表时间：
2008-05-07
期刊：
影响因子：
3.7
通讯作者：
Richter EA
中科院分区：
文献类型：
--
作者：
Jensen TE;Schjerling P;Viollet B;Wojtaszewski JF;Richter EA
AMPK是治疗代谢紊乱的一个很有前途的药理靶点，部分原因是它促进骨骼肌对非胰岛素依赖的葡萄糖摄取。在两种催化α-AMPK亚型中，α-2AMPK显然是在某些刺激刺激下刺激葡萄糖转运到肌肉中所必需的。相反，α1AMPK在骨骼肌中的明确功能尚未确定，可能是由于α-AMPK异构体信号冗余所致。通过在野生型和α-AMPK转基因小鼠肌肉中应用低强度抽动收缩和过氧化氢刺激来激活α1AMPK，而不是α2AMPK，本研究旨在确定α1AMPK需要什么条件来增加肌肉对葡萄糖的摄取。用H_2O_2(3 mM，20min)或抽动收缩(0.1ms脉冲，2 Hz，2min)刺激培养的比目鱼肌，检测野生型和肌特异性AMPK(KD)、α-1AMPK基因敲除和α-2AMPK基因敲除小鼠比目鱼肌的信号转导和2-脱氧葡萄糖摄取。与野生型相比，与野生型相比，H_2O_2增加了α-1和α-2AMPK的活性和Akt的磷酸化，并且H_2O_2刺激的葡萄糖摄取没有减少。相反，抽动收缩增加α-1AMPK活性，但不增加α-2AMPK活性，也不增加AKT或AS160的磷酸化。抽动刺激后，α1AMPK基因敲除肌肉和KD AMPK基因敲除肌肉的葡萄糖摄取显著降低，而α2AMPK基因敲除肌肉的葡萄糖摄取无明显变化。这些结果提供了强有力的遗传学证据，表明α1AMPK而不是α2AMPK、AKT或AS160是调节抽动收缩刺激的葡萄糖摄取所必需的。据我们所知，这是第一个显示α1AMPK在调节骨骼肌生理终点中的主要和关键作用的报告。相反，AMPK在过氧化氢刺激的肌肉葡萄糖摄取中并不是必需的，正如最近的研究所提出的那样。
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 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. 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 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. These 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.
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