TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice
TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice
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DOI：
10.1152/ajpendo.00204.2011
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发表时间：
2012-04-01
影响因子：
5.1
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Iwasaki, Hitoshi;Naka, Ayano;Shimano, Hitoshi
TFE3可调节小鼠肌肉代谢基因的表达，增加糖原储备，并增强胰岛素敏感性。AM J生理学内分泌代谢酶302：E896-E902,2012。-转录因子E3(TFE3)，一种bHLH转录因子，在免疫学和癌症中的作用已经得到了很好的表征。最近，我们报道了TFE3激活肝脏IRS-2和己糖激酶，参与胰岛素信号转导，改善糖尿病。然而，TFE3在其他器官中的作用还知之甚少。在这里，我们研究了TFE3对骨骼肌的影响，骨骼肌是参与葡萄糖代谢的重要器官。我们培育出了在骨骼肌中选择性表达TFE3的转基因小鼠。这些小鼠在成年前表现出轻微的生长加速，以及肌肉质量的逐渐增加。在TFE3转基因小鼠的肌肉中，糖原储存量是野生型小鼠的两倍多，这与葡萄糖代谢相关基因的上调有关，特别是葡萄糖转运蛋白4、己糖激酶II和糖原合成酶。因此，在这个转基因模型中，运动耐力得到了提高。此外，转基因小鼠的胰岛素敏感性增强，运动训练4wk后表现出更好的改善，这与IRS-2表达增加有关。TFE3对骨骼肌和肝脏葡萄糖代谢的影响是不同的，尽管它们在一定程度上是重叠的。TFE3在调节骨骼肌内代谢基因和葡萄糖代谢方面的潜在作用表明，它可能用于治疗代谢性疾病和提高运动耐力。
Iwasaki H, Naka A, Iida KT, Nakagawa Y, Matsuzaka T, Ishii K, Kobayashi K, Takahashi A, Yatoh S, Yahagi N, Sone H, Suzuki H, Yamada N, Shimano H. TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice. Am J Physiol Endocrinol Metab 302: E896-E902, 2012. First published January 31, 2012; doi: 10.1152/ajpendo.00204.2011.-The role of transcription factor E3 (TFE3), a bHLH transcription factor, in immunology and cancer has been well characterized. Recently, we reported that TFE3 activates hepatic IRS-2 and hexokinase, participates in insulin signaling, and ameliorates diabetes. However, the effects of TFE3 in other organs are poorly understood. Herein, we examined the effects of TFE3 on skeletal muscle, an important organ involved in glucose metabolism. We generated transgenic mice that selectively express TFE3 in skeletal muscles. These mice exhibit a slight acceleration in growth prior to adulthood as well as a progressive increase in muscle mass. In TFE3 transgenic muscle, glycogen stores were more than twofold than in wild-type mice, and this was associated with an upregulation of genes involved in glucose metabolism, specifically glucose transporter 4, hexokinase II, and glycogen synthase. Consequently, exercise endurance capacity was enhanced in this transgenic model. Furthermore, insulin sensitivity was enhanced in transgenic mice and exhibited better improvement after 4 wk of exercise training, which was associated with increased IRS-2 expression. The effects of TFE3 on glucose metabolism in skeletal muscle were different from that in the liver, although they did, in part, overlap. The potential role of TFE3 in regulating metabolic genes and glucose metabolism within skeletal muscle suggests that it may be used for treating metabolic diseases as well as increasing endurance in sport.