IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway
IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway
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DOI：
10.1007/s11010-017-3010-4
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发表时间：
2017-04
影响因子：
4.3
通讯作者：
Xiaoyu Mu;W. Qi;Yunzhang Liu;Jianfeng Zhou;Yun Li;Xiaozhi Rong;Ling Lu
中科院分区：
文献类型：
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作者：
Xiaoyu Mu;W. Qi;Yunzhang Liu;Jianfeng Zhou;Yun Li;Xiaozhi Rong;Ling Lu
胰岛素样生长因子II（IGF-II）可以刺激肌生成，并与骨骼肌分化密切相关。然而，这一过程的负调节剂的存在还没有得到很好的探索。在此，我们发现在成肌细胞中，IGF-II负调控过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1α）mRNA表达，而PGC-1α的组成性表达诱导成肌细胞分化。提示IGF-II对PGC-1α的负调节可能是IGF-II诱导肌细胞分化的负反馈机制。报告基因分析表明，IGF-II抑制基础PGC-1α启动子活性。阻断IGF-II信号通路可增加内源性PGC-1α水平。此外，药理学抑制PI 3激酶活性可阻止PGC-1α的下调，但这一过程不需要mTOR的激活。重要的是，进一步的分析表明，叉头转录因子FoxO 1有助于介导IGF-II对PGC-1启动子活性的影响。这些发现表明IGF-II通过PI 3 K-Akt-FoxO 1途径而非p38 MAPK或Erk 1/2 MAPK途径降低骨骼肌细胞中PGC-1α的表达。
Insulin-like growth factor II (IGF-II) can stimulate myogenesis and is critically involved in skeletal muscle differentiation. The presence of negative regulators of this process, however, is not well explored. Here, we showed that in myoblast cells, IGF-II negatively regulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA expression, while constitutive expression of PGC-1α induced myoblast differentiation. These results suggest that the negative regulation of PGC-1α by IGF-II may act as a negative feedback mechanism in IGF-II-induced myogenic differentiation. Reporter assays demonstrated that IGF-II suppresses the basal PGC-1α promoter activity. Blocking the IGF-II signaling pathway increased the endogenous PGC-1α levels. In addition, pharmacological inhibition of PI3 kinase activity prevented the downregulation of PGC-1α but the activation of mTOR was not required for this process. Importantly, further analysis showed that forkhead transcription factor FoxO1 contributes to mediating the effects of IGF-II on PGC-1 promoter activity. These findings indicate that IGF-II reduces PGC-1α expression in skeletal muscle cells through a mechanism involving PI3K–Akt–FoxO1 but not p38 MAPK or Erk1/2 MAPK pathways.