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Akt-mediated phosphorylation controls the activity of the Y-box protein MSY3 in skeletal muscle

机译：Akt介导的磷酸化控制骨骼肌中Y盒蛋白MSY3的活性

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Background The Y-box protein MSY3/Csda represses myogenin transcription in skeletal muscle by binding a highly conserved cis-acting DNA element located just upstream of the myogenin minimal promoter (myogHCE). It is not known how this MSY3 activity is controlled in skeletal muscle. In this study, we provide multiple lines of evidence showing that the post-translational phosphorylation of MSY3 by Akt kinase modulates the MSY3 repression of myogenin. Methods Skeletal muscle and myogenic C2C12 cells were used to study the effects of MSY3 phosphorylation in vivo and in vitro on its sub-cellular localization and activity, by blocking the IGF1/PI3K/Akt pathway, by Akt depletion and over-expression, and by mutating potential MSY3 phosphorylation sites. Results We observed that, as skeletal muscle progressed from perinatal to postnatal and adult developmental stages, MSY3 protein became gradually dephosphorylated and accumulated in the nucleus. This correlated well with the reduction of phosphorylated active Akt. In C2C12 myogenic cells, blocking the IGF1/PI3K/Akt pathway using LY294002 inhibitor reduced MSY3 phosphorylation levels resulting in its accumulation in the nuclei. Knocking down Akt expression increased the amount of dephosphorylated MSY3 and reduced myogenin expression and muscle differentiation. MSY3 phosphorylation by Akt in vitro impaired its binding at the MyogHCE element, while blocking Akt increased MSY3 binding activity. While Akt over-expression rescued myogenin expression in MSY3 overexpressing myogenic cells, ablation of the Akt substrate, (Ser126 located in the MSY3 cold shock domain) promoted MSY3 accumulation in the nucleus and abolished this rescue. Furthermore, forced expression of Akt in adult skeletal muscle induced MSY3 phosphorylation and myogenin derepression. Conclusions These results support the hypothesis that MSY3 phosphorylation by Akt interferes with MSY3 repression of myogenin circuit activity during muscle development. This study highlights a previously undescribed Akt-mediated signaling pathway involved in the repression of myogenin expression in myogenic cells and in mature muscle. Given the significance of myogenin regulation in adult muscle, the Akt/MSY3/myogenin regulatory circuit is a potential therapeutic target to counteract muscle degenerative disease.
机译：背景Y盒蛋白MSY3 / Csda通过结合位于肌生成素最小启动子（myogHCE）上游的高度保守的顺式作用DNA元件，抑制骨骼肌中肌生成素的转录。未知如何在骨骼肌中控制这种MSY3活性。在这项研究中，我们提供了多条证据，表明Akt激酶对MSY3的翻译后磷酸化可调节肌原蛋白的MSY3抑制。方法通过阻断IGF1 / PI3K / Akt途径，Akt耗竭和过度表达以及通过抑制骨骼肌和肌源性C2C12细胞研究MSY3磷酸化在体内和体外对其亚细胞定位和活性的影响。突变潜在的MSY3磷酸化位点。结果我们观察到，随着骨骼肌从围产期发展到产后和成人发育阶段，MSY3蛋白逐渐被去磷酸化并积累在细胞核中。这与磷酸化的活性Akt的减少很好地相关。在C2C12肌细胞中，使用LY294002抑制剂阻断IGF1 / PI3K / Akt途径可降低MSY3磷酸化水平，从而导致其在细胞核中蓄积。降低Akt的表达增加了去磷酸化MSY3的数量，并减少了肌成蛋白的表达和肌肉分化。 Akt在体外将MSY3磷酸化会削弱其与MyogHCE元件的结合，而阻断Akt则会增加MSY3的结合活性。虽然Akt的过表达可以挽救过表达MSY3的成肌细胞中肌生成素的表达，但消融Akt底​​物（位于MSY3冷休克域中的Ser126）促进了MSY3在细胞核中的积累，并废除了这种拯救。此外，在成人骨骼肌中强制表达Akt会诱导MSY3磷酸化和肌生成素抑制。结论这些结果支持这样的假说，即Akt产生的MSY3磷酸化会干扰肌肉发育过程中MSY3对肌原蛋白回路活性的抑制。这项研究突出了以前未描述的Akt介导的信号通路，参与了成肌细胞和成熟肌肉中肌生成素表达的抑制。考虑到成年肌中肌生成素调节的重要性，Akt / MSY3 /肌生成素调节回路是抵消肌肉退行性疾病的潜在治疗靶标。

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