Decrotonylation of AKT1 promotes AKT1 phosphorylation and activation during myogenic differentiation,Journal of Advanced Research

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Decrotonylation of AKT1 promotes AKT1 phosphorylation and activation during myogenic differentiation
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2022-10-18 , DOI: 10.1016/j.jare.2022.10.005
Zhengyu Qian ₁ , Jingwei Ye ₁ , Jinteng Li ₁ , Yunshu Che ₁ , Wenhui Yu ₁ , Peitao Xu ₁ , Jiajie Lin ₁ , Feng Ye ₂ , Xiaojun Xu ₁ , Zepeng Su ₁ , Dateng Li ₃ , Zhongyu Xie ₁ , Yanfeng Wu ₄ , Huiyong Shen ₅

Affiliation

Introduction

Myogenic differentiation plays an important role in pathophysiological processes including muscle injury and regeneration, as well as muscle atrophy. A novel type of posttranslational modification, crotonylation, has been reported to play a role in stem cell differentiation and disease. However, the role of crotonylation in myogenic differentiation has not been clarified.

Objectives

This study aims to find the role of crotonylation during myogenic differentiation and explore whether it is a potential target in myogenic dysfunction disease.

Methods

C2C12 cell line and skeletal muscle mesenchymal progenitors of Mus musculus were used for myogenic process study in vitro, while muscle injury model of mice was used for in vivo muscle regeneration study. Mass spectrometry favored in discovery of potential target protein of crotonylation and its specific sites.

Results

We confirmed the gradual decrease in total protein crotonylation level during muscle differentiation and found decreased crotonylation of AKT1, which facilitated an increase in AKT1 phosphorylation. Then we verified that crotonylation of AKT1 at specific sites weakened its binding with PDK1 and impaired its phosphorylation. In addition, we found that increased expression of the crotonylation eraser HDAC3 decreased AKT1 crotonylation levels during myogenic differentiation, jointly promoting myogenic differentiation.

Conclusion

Our study highlights the important role of decrotonylation of AKT1 in the process of muscle differentiation, where it aids the phosphorylation and activation of AKT1 and promotes myogenic differentiation. This is of great significance for exploring the pathophysiological process of muscle injury repair and sarcopenia.

中文翻译：

AKT1 去巴豆酰化促进肌原性分化过程中 AKT1 磷酸化和激活

介绍

肌源性分化在肌肉损伤和再生以及肌肉萎缩等病理生理过程中发挥着重要作用。据报道，一种新型的翻译后修饰——巴豆酰化在干细胞分化和疾病中发挥作用。然而，巴豆酰化在肌原性分化中的作用尚未阐明。

目标

本研究旨在寻找巴豆酰化在肌源性分化过程中的作用，并探讨其是否是肌源性功能障碍疾病的潜在靶点。

方法

采用小家鼠C2C12细胞系和骨骼肌间充质祖细胞进行体外成肌过程研究，采用小鼠肌肉损伤模型进行体内肌肉再生研究。质谱有利于发现巴豆酰化的潜在靶蛋白及其特定位点。

结果

我们证实了肌肉分化过程中总蛋白巴豆酰化水平逐渐下降，并发现 AKT1 巴豆酰化水平降低，这促进了 AKT1 磷酸化的增加。然后我们验证了 AKT1 在特定位点的巴豆酰化削弱了其与 PDK1 的结合并损害了其磷酸化。此外，我们发现巴豆酰化擦除器HDAC3表达增加会降低肌原性分化过程中AKT1巴豆酰化水平，共同促进肌原性分化。