在小鼠骨骼肌中，通过抽搐收缩刺激葡萄糖摄取需要激活AMPKα1，但通过过氧化氢刺激则不需要。
AMPK alpha1 activation is required for stimulation of glucose uptake by twitch contraction, but not by H2O2, in mouse skeletal muscle.
作者信息
Jensen Thomas E, Schjerling Peter, Viollet Benoit, Wojtaszewski Jørgen F P, Richter Erik A
机构信息
Molecular Physiology Group, Copenhagen Muscle Research Centre, Department of Exercise and Sport Sciences, Section of Human Physiology, University of Copenhagen, Copenhagen, Denmark.
出版信息
PLoS One. 2008 May 7;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 H(2)O(2) 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 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), alpha(1) AMPK knockout or alpha(2) AMPK knockout mice. H(2)O(2) increased the activity of both alpha(1) and alpha(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 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 H(2)O(2)-stimulated muscle glucose uptake, as proposed by recent studies.
背景
AMPK是一种与代谢紊乱相关的有前景的药理学靶点，部分原因是其在骨骼肌中具有促进非胰岛素依赖性葡萄糖摄取的作用。在两种催化性α-AMPK亚型中，α(2) AMPK显然是某些刺激促进葡萄糖转运至肌肉所必需的。相比之下，α(1) AMPK在骨骼肌中的明确功能尚未确定，这可能是由于α-AMPK亚型信号冗余所致。通过对野生型和α-AMPK转基因小鼠肌肉施加低强度抽搐收缩和H₂O₂刺激以激活α(1) AMPK而非α(2) AMPK，本研究旨在确定α(1) AMPK在增加肌肉葡萄糖摄取中发挥作用所需的条件。
方法/主要发现：在用H₂O₂（3 mM，20分钟）或抽搐收缩（0.1毫秒脉冲，2赫兹，2分钟）刺激后，测量野生型和肌肉特异性激酶失活的AMPK（KD）、α(1) AMPK基因敲除或α(2) AMPK基因敲除小鼠的比目鱼肌中的信号传导和2-脱氧葡萄糖摄取。H₂O₂除了增加Akt磷酸化外，还增加了α(1)和α(2) AMPK的活性，与野生型相比，在任何AMPK转基因小鼠模型中，H₂O₂刺激的葡萄糖摄取均未降低。相比之下，抽搐收缩增加了α(1) AMPK的活性，但未增加α(2) AMPK的活性，也未增加Akt或AS160的磷酸化。抽搐刺激后，α(1) AMPK基因敲除和KD AMPK肌肉中的葡萄糖摄取明显降低，但α(2) AMPK基因敲除肌肉中的葡萄糖摄取未降低。
结论/意义：这些结果提供了有力的遗传学证据，表明α(1) AMPK而非α(2) AMPK、Akt或AS160是调节抽搐收缩刺激的葡萄糖摄取所必需的。据我们所知，这是第一份显示α(1) AMPK在调节骨骼肌生理终点中起主要和关键作用的报告。相比之下，正如最近研究所提出的，AMPK对于H₂O₂刺激的肌肉葡萄糖摄取并非必不可少。
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