Leucine modulates contraction- and insulin-stimulated glucose transport and upstream signaling events in rat skeletal muscle
Leucine modulates contraction- and insulin-stimulated glucose transport and upstream signaling events in rat skeletal muscle
复制标题
DOI：
10.1152/japplphysiol.00420.2009
复制
发表时间：
2010-02-01
影响因子：
3.3
通讯作者：
Hayashi, Tatsuya
中科院分区：
文献类型：
--
作者：
Iwanaka, Nobumasa;Egawa, Tatsuro;Hayashi, Tatsuya
Iwanaka N，Ekawa T，Satoubu N，Karaike K，Ma X，Masuda S，Hayashi T。亮氨酸调节大鼠骨骼肌中收缩和胰岛素刺激的葡萄糖转运和上游信号传导事件。 J Appl Physiol 108: 274-282, 2010。首次发表于 2009 年 11 月 25 日； doi:10.1152/japplphyol.00420.2009.-亮氨酸对肌肉中的葡萄糖代谢具有深远的影响；然而，亮氨酸对肌肉中葡萄糖转运的影响尚未得到充分记录。我们在体外研究了亮氨酸对离体大鼠滑车上肌收缩和胰岛素刺激的葡萄糖转运的影响。在缺乏胰岛素的情况下，强直性收缩会增加 3-O-甲基-D-葡萄糖 (3-MG) 转运和 5'-AMP 激活蛋白激酶 (AMPK) 催化 α 亚基的 Thr(172) 磷酸化，AMPK 是导致不依赖于胰岛素的葡萄糖转运的信号中介。亮氨酸（2 mM，30 分钟）显着增强收缩刺激的 3-MG 转运和 AMPK 磷酸化，同时增加 p70 S6 激酶 (p70S6K) Thr(389) 的磷酸化。 STO-609 阻断 Ca-21/钙调蛋白依赖性蛋白激酶激酶 (CaMKK) 或雷帕霉素阻断 p70S6K 可以取消亮氨酸对 3-MG 转运和 AMPK 磷酸化的刺激作用。另一方面，亮氨酸会减弱胰岛素刺激的 3-MG 转运并减少胰岛素刺激的 Akt Thr(473) 磷酸化。亮氨酸增加胰岛素刺激的 p70S6K Thr(389) 磷酸化，并增强胰岛素受体底物 1 (IRS1) Ser(636/639) 的抑制性磷酸化。此外，雷帕霉素消除了亮氨酸对胰岛素刺激的 3-MG 转运和 IRS 磷酸化的影响。这些结果表明，亮氨酸通过激活哺乳动物雷帕霉素靶点 (mTOR)/p70S6K 信号传导，激活骨骼肌中收缩刺激的葡萄糖转运并抑制胰岛素刺激的葡萄糖转运。收缩刺激的 AMPK Thr(172) 磷酸化和胰岛素刺激的 IRS1 Ser(636/639) 磷酸化的增强可能分别是亮氨酸的这些相反作用的原因。
Iwanaka N, Egawa T, Satoubu N, Karaike K, Ma X, Masuda S, Hayashi T. Leucine modulates contraction- and insulin-stimulated glucose transport and upstream signaling events in rat skeletal muscle. J Appl Physiol 108: 274-282, 2010. First published November 25, 2009; doi:10.1152/japplphysiol.00420.2009.-Leucine has profound effects on glucose metabolism in muscle; however, the effects of leucine on glucose transport in muscle have not been well documented. We investigated the effects of leucine on contraction- and insulin-stimulated glucose transport in isolated rat epitrochlearis muscle in vitro. In the absence of insulin, tetanic contraction increased 3-O-methyl-D-glucose (3-MG) transport and Thr(172) phosphorylation of the catalytic alpha-subunit of 5'-AMP-activated protein kinase (AMPK), a signaling intermediary leading to insulin-independent glucose transport. Leucine (2 mM, 30 min) significantly enhanced contraction- stimulated 3-MG transport and AMPK phosphorylation, accompanied by increased phosphorylation of p70 S6 kinase (p70S6K) Thr(389). The stimulatory effects of leucine on 3-MG transport and AMPK phosphorylation were canceled by STO-609 blockade of Ca-21/calmodulin-dependent protein kinase kinase (CaMKK) or rapamycin blockade of p70S6K. On the other hand, leucine blunted insulin-stimulated 3-MG transport and reduced insulin-stimulated Akt Thr(473) phosphorylation. Leucine increased insulin-stimulated p70S6K Thr(389) phosphorylation and enhanced the inhibitory phosphorylation of the insulin receptor substrate 1 (IRS1) Ser(636/639). Furthermore, the effects of leucine on insulin-stimulated 3-MG transport and IRS phosphorylation were abolished by rapamycin. These results indicate that leucine activates contraction- stimulated glucose transport and inhibits insulin-stimulated glucose transport in skeletal muscle by activating mammalian target of rapamycin (mTOR)/p70S6K signaling. Enhanced increases in contraction- stimulated AMPK Thr(172) phosphorylation and insulin-stimulated IRS1 Ser(636/639) phosphorylation might be responsible for these opposing effects of leucine, respectively.