Down-Regulation of Akt/Mammalian Target of Rapamycin Signaling Pathway in Response to Myostatin Overexpression in Skeletal Muscle
Down-Regulation of Akt/Mammalian Target of Rapamycin Signaling Pathway in Response to Myostatin Overexpression in Skeletal Muscle
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DOI：
10.1210/en.2008-0959
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发表时间：
2009-01-01
期刊：
影响因子：
4.8
通讯作者：
Freyssenet, Damien
中科院分区：
文献类型：
--
作者：
Amirouche, Adel;Durieux, Anne-Cecile;Freyssenet, Damien
肌生长抑制素是tgf - β家族的一员，已被确定为胚胎肌肉发生和早期出生后骨骼肌生长的主要调节因子。然而，累积的证据也表明骨骼肌质量的改变与肌肉生长抑制素表达的失调有关，肌肉生长抑制素可能导致成年期肌肉质量的减少。Akt通路的两个主要分支与骨骼肌质量的调节有关，Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路控制蛋白质合成，Akt/叉头盒O（FOXO）通路控制蛋白质降解。在这里，我们通过表明肌生长抑制素负调控Akt/mTOR信号通路，进一步深入了解肌生长抑制素调节骨骼肌质量的机制。将肌生长抑制素表达载体电转移至雄性大鼠胫骨前肌后7 d，肌生长抑制素蛋白水平升高，骨骼肌质量下降。通过RT-PCR和免疫印迹分析，我们发现肌生长抑制素过表达对改变泛素-蛋白酶体通路无效。相反，肌生长抑制素作为Akt/mTOR通路的负调控因子。数据显示，肌生长抑制素基因电转移7天后，Thr308上的Akt磷酸化、Thr1462上的结节硬化复合体2磷酸化、Ser235/236上的核糖体蛋白S6磷酸化和Thr37/46上的4E-BP1磷酸化均减弱。这些数据支持Akt/mTOR信号是肌肉萎缩过程中肌生长抑制素功能的关键靶点的结论，揭示了肌生长抑制素在蛋白质代谢中的新作用，更具体地说，是在骨骼肌翻译调节中的新作用。（内分泌学150:286-294,2009）
Myostatin, a member of the TGF-beta family, has been identified as a master regulator of embryonic myogenesis and early postnatal skeletal muscle growth. However, cumulative evidence also suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression and that myostatin may contribute to muscle mass loss in adulthood. Two major branches of the Akt pathway are relevant for the regulation of skeletal muscle mass, the Akt/mammalian target of rapamycin (mTOR) pathway, which controls protein synthesis, and the Akt/forkhead box O(FOXO) pathway, which controls protein degradation. Here, we provide further insights into the mechanisms by which myostatin regulates skeletal muscle mass by showing that myostatin negatively regulates Akt/mTOR signaling pathway. Electrotransfer of a myostatin expression vector into the tibialis anterior muscle of Sprague Dawley male rats increased myostatin protein level and decreased skeletal muscle mass 7 d after gene electrotransfer. Using RT-PCR and immunoblot analyses, we showed that myostatin overexpression was ineffective to alter the ubiquitin-proteasome pathway. By contrast, myostatin acted as a negative regulator of Akt/mTOR pathway. This was supported by data showing that the phosphorylation of Akt on Thr308, tuberous sclerosis complex 2 on Thr1462, ribosomal protein S6 on Ser235/236, and 4E-BP1 on Thr37/46 was attenuated 7 d after myostatin gene electrotransfer. The data support the conclusion that Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. (Endocrinology 150: 286-294, 2009)