TNF induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not AKT-Foxo1/3 signaling
TNF induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not AKT-Foxo1/3 signaling
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DOI：
10.1152/ajpcell.00041.2008
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发表时间：
2008-10-01
影响因子：
5.5
通讯作者：
Reid, Michael B.
中科院分区：
文献类型：
--
作者：
Moylan, Jennifer S.;Smith, Jeffrey D.;Reid, Michael B.
小鼠饥饿引起的肌肉萎缩模型表明，蛋白激酶B （AKT）功能降低可上调萎缩相关基因atrogin-1/MAFbx （atrogin）。其机制涉及叉头转录因子Foxo1和Foxo3的抑制释放。atrogin mRNA的升高也与炎症分解代谢状态下TNF的升高相对应，包括癌症和慢性心力衰竭。外源性肿瘤坏死因子（TNF）使atroginmrna在体内外升高。我们使用TNF处理的C2C12肌管来验证AKT-Foxo1/3信号通路介导TNF调节atrogin mRNA的假设。在这里，我们证实暴露于TNF会增加atrogin mRNA（+125%）。我们也证实了典型的akt介导的atrogin在C2C12肌管中是活跃的。wortmannin抑制磷酸肌醇-3激酶(PI3K)/AKT信号通路降低AKT磷酸化（-87%），增加atrogin mRNA（+340%）。胰岛素样生长因子（IGF）激活增加AKT磷酸化（+126%），减少atrogin mRNA（-15%）。虽然AKT的调控是完整的，但我们的数据表明它不介导TNF对atrogin的作用。TNF增加AKT磷酸化（+50%），IGF刺激AKT不阻止TNF诱导atrogin mRNA。TNF似乎也不通过Foxo1/3蛋白发出信号。TNF对Foxo1/3 mRNA和Foxo1/3核定位无影响。相反，TNF增加核Foxo4蛋白（+55%）。靶向Foxo4 mRNA两个不同区域的小干扰RNA寡核苷酸减少了tnf诱导的atrogin mRNA的增加（-34%和-32%）。我们得出结论，TNF通过Foxo4增加atroginmrna，而不依赖于AKT。这些结果表明，炎症分解代谢状态可能在存在足够的生长因子和营养的情况下持续存在。
Murine models of starvation-induced muscle atrophy demonstrate that reduced protein kinase B (AKT) function upregulates the atrophy-related gene atrogin-1/MAFbx (atrogin). The mechanism involves release of inhibition of Forkhead transcription factors, namely Foxo1 and Foxo3. Elevated atrogin mRNA also corresponds with elevated TNF in inflammatory catabolic states, including cancer and chronic heart failure. Exogenous tumor necrosis factor (TNF) increases atrogin mRNA in vivo and in vitro. We used TNF-treated C2C12 myotubes to test the hypothesis that AKT-Foxo1/3 signaling mediates TNF regulation of atrogin mRNA. Here we confirm that exposure to TNF increases atrogin mRNA (+125%). We also confirm that canonical AKT-mediated regulation of atrogin is active in C2C12 myotubes. Inhibition of phosphoinositol-3 kinase (PI3K)/AKT signaling with wortmannin reduces AKT phosphorylation (-87%) and increases atrogin mRNA (+340%). Activation with insulin-like growth factor (IGF) increases AKT phosphorylation (+126%) and reduces atrogin mRNA (-15%). Although AKT regulation is intact, our data suggest it does not mediate TNF effects on atrogin. TNF increases AKT phosphorylation (+50%) and stimulation of AKT with IGF does not prevent TNF induction of atrogin mRNA. Nor does TNF appear to signal through Foxo1/3 proteins. TNF has no effect on Foxo1/3 mRNA or Foxo1/3 nuclear localization. Instead, TNF increases nuclear Foxo4 protein (+55%). Small interfering RNA oligos targeted to two distinct regions of Foxo4 mRNA reduce the TNF-induced increase in atrogin mRNA (-34% and -32%). We conclude that TNF increases atrogin mRNA independent of AKT via Foxo4. These results suggest a mechanism by which inflammatory catabolic states may persist in the presence of adequate growth factors and nutrition.