Guo Yuting, Meng Jin, Tang Yinglong, Wang Ting, Wei Bin, Feng Run, Gong Bing, Wang Huiwen, Ji Guangju, Lu Zhongbing
College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Arch Biochem Biophys. 2016 Jun 15;600:56-60. doi: 10.1016/j.abb.2016.04.015. Epub 2016 Apr 29.
AMP-activated protein kinase (AMPK) is a master regulator of skeletal muscle metabolic pathways. Recently, AMPK activation by AICAR has been shown to increase myofibrillar protein degradation in C2C12 myotubes via stimulating autophagy and ubiquitin proteasome system. However, the impact of AMPKα on denervation induced muscle atrophy has not been tested. In this study, we performed sciatic denervation on hind limb muscles in both wild type (WT) and AMPKα2(-/-) mice. We found that AMPKα was phosphorylated in atrophic muscles following denervation. In addition, deletion of AMPKα2 significantly attenuated denervation induced skeletal muscle wasting and protein degradation, as evidenced by preserved muscle mass and myofiber area, as well as lower levels of ubiquitinated protein, Atrogin-1 and MuRF-1 expression, and LC3-II/I ratio in tibial anterior (TA) muscles. Interestingly, the phosphorylated FoxO3a at Ser253 was significantly decreased in atrophic TA muscles, which was preserved in AMPKα2(-/-) mice. Collectively, our data support the notion that the activation of AMPKα2 contributes to the atrophic effects of denervation.
AMP激活的蛋白激酶（AMPK）是骨骼肌代谢途径的主要调节因子。最近，已表明AICAR激活AMPK可通过刺激自噬和泛素蛋白酶体系统增加C2C12肌管中的肌原纤维蛋白降解。然而，AMPKα对去神经支配诱导的肌肉萎缩的影响尚未得到测试。在本研究中，我们对野生型（WT）和AMPKα2基因敲除小鼠的后肢肌肉进行了坐骨神经去神经支配。我们发现去神经支配后萎缩肌肉中的AMPKα被磷酸化。此外，AMPKα2的缺失显著减轻了去神经支配诱导的骨骼肌萎缩和蛋白质降解，这通过保留肌肉质量和肌纤维面积以及降低胫前（TA）肌肉中泛素化蛋白、Atrogin-1和MuRF-1的表达水平以及LC3-II/I比率得以证明。有趣的是，在萎缩的TA肌肉中，Ser253位点磷酸化的FoxO3a显著减少，而在AMPKα2基因敲除小鼠中则得以保留。总体而言，我们的数据支持AMPKα2的激活促成去神经支配萎缩效应这一观点。
