Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance-猫眼课题宝

DOI：

10.4161/cc.29272

发表时间：

2014-06

期刊：

Cell Cycle

影响因子：

4.3

通讯作者：

中科院分区：

生物学3区

文献类型：

作者：

Rodrigo Troncoso;F. Paredes;V. Parra;D. Gatica;César Vásquez-Trincado;Clara Quiroga;R. Bravo-Sagua;Camila López-Crisosto;Andrea E. Rodríguez;Alejandra P. Oyarzún;G. Kroemer;S. Lavandero

糖皮质激素，如地塞米松，通过泛素-蛋白酶体系统促进蛋白质分解。然而，自噬在糖皮质激素依赖性萎缩中的细胞器和蛋白质周转中的作用仍然未知。在这里，我们表明，地塞米松刺激L 6肌管中的自噬依赖于蛋白激酶，AMPK和糖皮质激素受体活性的早期激活。地塞米松增加了几种自噬基因的表达，包括ATG 5，LC 3，BECN 1和SQSTM 1，并触发了与DNM 1 L蛋白水平增加相关的AMPK依赖性线粒体片段化。这一过程是地塞米松诱导的线粒体自噬所必需的。Mdivi-1对线粒体片段化的抑制导致地塞米松诱导的自噬/线粒体自噬被破坏。此外，Mdivi-1增加了与萎缩程序相关的基因的表达，表明线粒体自噬可以作为地塞米松处理的L 6肌管的质量控制过程的一部分。总的来说，这些数据表明地塞米松诱导的自噬/线粒体自噬在调节肌肉萎缩程序中的新作用。

Glucocorticoids, such as dexamethasone, enhance protein breakdown via ubiquitin–proteasome system. However, the role of autophagy in organelle and protein turnover in the glucocorticoid-dependent atrophy program remains unknown. Here, we show that dexamethasone stimulates an early activation of autophagy in L6 myotubes depending on protein kinase, AMPK, and glucocorticoid receptor activity. Dexamethasone increases expression of several autophagy genes, including ATG5, LC3, BECN1, and SQSTM1 and triggers AMPK-dependent mitochondrial fragmentation associated with increased DNM1L protein levels. This process is required for mitophagy induced by dexamethasone. Inhibition of mitochondrial fragmentation by Mdivi-1 results in disrupted dexamethasone-induced autophagy/mitophagy. Furthermore, Mdivi-1 increases the expression of genes associated with the atrophy program, suggesting that mitophagy may serve as part of the quality control process in dexamethasone-treated L6 myotubes. Collectively, these data suggest a novel role for dexamethasone-induced autophagy/mitophagy in the regulation of the muscle atrophy program.

Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance

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