Effects of Pharmacological AMP Deaminase Inhibition and Ampd1 Deletion on Nucleotide Levels and AMPK Activation in Contracting Skeletal Muscle
Effects of Pharmacological AMP Deaminase Inhibition and Ampd1 Deletion on Nucleotide Levels and AMPK Activation in Contracting Skeletal Muscle
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DOI：
10.1016/j.chembiol.2014.09.013
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发表时间：
2014-11-20
影响因子：
--
通讯作者：
Rider, Mark H.
中科院分区：
文献类型：
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作者：
Plaideau, Catheline;Lai, Yu-Chiang;Rider, Mark H.
AMP活化蛋白激酶（AMPK）在调节代谢和能量平衡中起着重要作用。它通过感知AMP：ATP比率的波动来实现其功能。AMP脱氨酶（AMPD）将AMP转化为IMP，AMPD 1同工酶在骨骼肌中表达。在这里，药理学抑制和AMPD的基因缺失的影响进行了检查，在收缩肌肉。药理学AMPD抑制增强AMP，AMP：ATP比，AMPK Thr172和乙酰辅酶A羧化酶（ACC）Ser218磷酸化由电刺激诱导的上升，而不影响葡萄糖转运。在孵育的伸趾长肌和比目鱼肌肌肉Ampd1基因敲除小鼠，AMP水平和AMP：ATP比电刺激的增加大大增强与野生型小鼠的肌肉相比，而增强AMPK激活是温和的，只观察到比目鱼肌，这表明控制因素以外的腺嘌呤核苷酸的变化。AMPD抑制剂可能是在ATP耗竭期间增强细胞和组织中AMPK活化的有用工具。
AMP-activated protein kinase (AMPK) plays a central role in regulating metabolism and energy homeostasis. It achieves its function by sensing fluctuations in the AMP: ATP ratio. AMP deaminase (AMPD) converts AMP into IMP, and the AMPD1 isoenzyme is expressed in skeletal muscles. Here, effects of pharmacological inhibition and genetic deletion of AMPD were examined in contracting skeletalmuscles. Pharmacological AMPD inhibition potentiated rises in AMP, AMP: ATP ratio, AMPK Thr172, and acetyl-CoA carboxylase (ACC) Ser218 phosphorylation induced by electrical stimulation, without affecting glucose transport. In incubated extensor digitorum longus and soleus muscles from Ampd1 knockout mice, increases in AMP levels and AMP: ATP ratio by electrical stimulation were potentiated considerably compared with muscles from wild-type mice, whereas enhanced AMPK activation was moderate and only observed in soleus, suggesting control by factors other than changes in adenine nucleotides. AMPD inhibitors could be useful tools for enhancing AMPK activation in cells and tissues during ATP-depletion.