The Role of AMP kinase in Exercise-Stimulated Insulin Sensitivity in Skeletal Muscle

1.骨骼肌表达5‘-AMP激活的蛋白激酶(AMPK)的两个催化亚基α1和α2，AMPK与运动刺激的代谢事件有关，如葡萄糖转运、脂肪酸氧化和胰岛素敏感性。AMPK在新陈代谢应激反应中被激活，如收缩、缺氧和氧化磷酸化的抑制。在这项研究中，我们假设急性氧化应激刺激骨骼肌中的AMPK。我们的数据表明，氧化应激通过AMP不依赖的机制激活骨骼肌中的α1，而不是α2，并导致葡萄糖转运速率和乙酰辅酶A羧化酶(ACC)磷酸化的增加。2.肌肉收缩激活α2，但这种激活可能在α1激活的情况下发生，这表明α2是收缩诱导的代谢事件的主要亚型。在本研究中，我们发现：1)AMPKα1是…激活的主要异构体在低强度收缩肌中有更多的AMP非依赖性的磷酸化，2)在高强度收缩肌中AMPKα2被AMP依赖的机制激活，3)每种异构体的激活都促进了骨骼肌中葡萄糖的转运和ACC的磷酸化。3.我们先前报道了在肝脏过度表达瘦素(LepTg)的转基因小鼠表现出高瘦素血症和胰岛素敏感性增强。在这项研究中，我们发现在LepTg比目鱼肌中，AMPK的磷酸化水平随着组织甘油三酯的降低而慢性增强。尽管先前存在高瘦素血症，但高脂饮食(HFD)喂养的LepTg会出现肥胖、胰岛素抵抗和高脂血症。同时，常规饲料喂养的LepTg中升高的比目鱼肌AMPK被减弱，而服用HFD的患者组织甘油三酯增加。常规饮食替代高脂饮食可使LepTg中的比目鱼肌AMPK显著恢复，体重减重率更高，胰岛素敏感性恢复。我们得出结论，LepTg中的比目鱼肌AMPK与其胰岛素敏感性在饮食调整下的变化是平行的，这表明骨骼肌AMPK活性与瘦素的敏感性密切相关。较少

1.Skeletal muscle expresses two catalytic subunits, alpha1 and alpha2, of the 5'-AMP-activated protein kinase (AMPK), which is implicated in exercise-stimulated metabolic events, such as glucose transport, fatty acid oxidation and insulin sensitivity. AMPK is activated in response to metabolic stresses, such as contraction, hypoxia, and the inhibition of oxidative phosphorylation. In this research we hypothesized that acute oxidative stress stimulates AMPK in skeletal muscle. Our data suggest that oxidative stress activates alpha1, but not alpha2, in skeletal muscle via an AMP-independent mechanism and leads to increases in the rate of glucose transport and acetyl CoA carboxylase (ACC) phosphorylation.2.Muscle contraction activates alpha2, but this activation may occur with or without activation of alpha1, suggesting that alpha2 is the major isoform responsible for contraction-induced metabolic events. In this research we found that 1)AMPK alpha1 is the predominant isoform activated by … More AMP-independent phosphorylation in low-intensity contracting muscle, 2)AMPK alpha2 is activated by an AMP-dependent mechanism in high-intensity contracting muscle, and 3)activation of each isoform enhances glucose transport and ACC phosphorylation in skeletal muscle.3.We previously reported that transgenic mice overexpressing leptin in the liver (LepTg) exhibit hyperleptinemia and enhanced insulin sensitivity. In this research we found that phosphorylation of AMPK was chronically augmented in LepTg soleus, with a concomitant decrease in tissue triglyceride. Despite preexisting hyperleptinemia, high-fat diet (HFD)-fed LepTg developed obesity, insulin-resistance, and hyperlipidemia. In parallel, elevated soleus AMPK in regular diet-fed LepTg was attenuated, and tissue triglyceride was increased in those given HFD. Substitution of HFD with regular diet caused a robust recovery of soleus AMPK in LepTg, with a higher rate of body weight reduction and a regain of insulin sensitivity. We conclude that soleus AMPK in LepTg changes in parallel with its insulin sensitivity under dietary modification, suggesting a close association between skeletal muscle AMPK activity and sensitivity to leptin. Less