Plenary Lecture Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism
Plenary Lecture Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism
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DOI：
10.1017/s0029665110003915
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发表时间：
2011-02-01
影响因子：
7
通讯作者：
Hardie, D. Grahame
中科院分区：
文献类型：
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作者：
Hardie, D. Grahame
amp活化蛋白激酶（AMPK）是细胞能量状态的传感器，在细胞和全身水平上调节能量平衡。虽然它无处不在表达，但其功能在骨骼肌中得到了最好的理解。AMPK含有可逆结合AMP或ATP的位点，细胞AMP: ATP比率增加（信号细胞能量状态下降）打开激酶。因此，在肌肉中，AMPK的激活是由持续收缩触发的，并且在从阻力运动到耐力运动的过渡中发生的代谢变化中似乎特别重要。AMPK一旦被激活，就会开启产生ATP的分解代谢过程，同时关闭短期内不需要的能量消耗过程。因此，它会剧烈激活葡萄糖摄取（通过促进转运体GLUT4向膜的易位）和脂肪酸氧化，同时关闭糖原合成和蛋白质合成（后者通过哺乳动物雷帕霉素靶通路失活）。延长的AMPK激活也会导致一些对耐力运动的慢性适应，如GLUT4表达和线粒体生物发生的增加。AMPK含有一个糖原结合结构域，使一个亚片段结合到糖原颗粒的表面，它可以通过磷酸化糖原合成酶来抑制糖原合成。我们已经证明AMPK被暴露在糖原中的非还原末端所抑制。我们正在研究这样一种假设，即当运动后糖原消耗殆尽时，糖原合成被迅速激活，但当糖原储存得到补充时，糖原合成又被关闭。
The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP: ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-of-rapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished.