Kjøbsted Rasmus, Munk-Hansen Nanna, Birk Jesper B, Foretz Marc, Viollet Benoit, Björnholm Marie, Zierath Juleen R, Treebak Jonas T, Wojtaszewski Jørgen F P
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diabetes. 2017 Mar;66(3):598-612. doi: 10.2337/db16-0530. Epub 2016 Oct 26.
Earlier studies have demonstrated that muscle insulin sensitivity to stimulate glucose uptake is enhanced several hours after an acute bout of exercise. Using AICAR, we recently demonstrated that prior activation of AMPK is sufficient to increase insulin sensitivity in mouse skeletal muscle. Here we aimed to determine whether activation of AMPK is also a prerequisite for the ability of muscle contraction to increase insulin sensitivity. We found that prior in situ contraction of m. extensor digitorum longus (EDL) and treadmill exercise increased muscle and whole-body insulin sensitivity in wild-type (WT) mice, respectively. These effects were not found in AMPKα1α2 muscle-specific knockout mice. Prior in situ contraction did not increase insulin sensitivity in m. soleus from either genotype. Improvement in muscle insulin sensitivity was not associated with enhanced glycogen synthase activity or proximal insulin signaling. However, in WT EDL muscle, prior in situ contraction enhanced insulin-stimulated phosphorylation of TBC1D4 Thr and Ser Such findings are also evident in prior exercised and insulin-sensitized human skeletal muscle. Collectively, our data suggest that the AMPK-TBC1D4 signaling axis is likely mediating the improved muscle insulin sensitivity after contraction/exercise and illuminates an important and physiologically relevant role of AMPK in skeletal muscle.
早期研究表明，急性运动发作数小时后，肌肉对刺激葡萄糖摄取的胰岛素敏感性会增强。我们最近使用AICAR证明，AMPK的预先激活足以提高小鼠骨骼肌的胰岛素敏感性。在这里，我们旨在确定AMPK的激活是否也是肌肉收缩增加胰岛素敏感性能力的先决条件。我们发现，事先对野生型（WT）小鼠的趾长伸肌（EDL）进行原位收缩和跑步机运动，分别增加了肌肉和全身的胰岛素敏感性。在AMPKα1α2肌肉特异性敲除小鼠中未发现这些效应。事先进行原位收缩并未增加两种基因型小鼠比目鱼肌的胰岛素敏感性。肌肉胰岛素敏感性的改善与糖原合酶活性增强或近端胰岛素信号传导无关。然而，在WT EDL肌肉中，事先进行原位收缩增强了胰岛素刺激的TBC1D4苏氨酸和丝氨酸的磷酸化。这些发现在先进行运动且胰岛素敏感的人体骨骼肌中也很明显。总体而言，我们的数据表明，AMPK-TBC1D4信号轴可能介导了收缩/运动后肌肉胰岛素敏感性的改善，并阐明了AMPK在骨骼肌中的重要生理相关作用。
