Impaired autophagic flux contributes to muscle atrophy in obesity by affecting muscle degradation and regeneration
Impaired autophagic flux contributes to muscle atrophy in obesity by affecting muscle degradation and regeneration
复制标题
自噬通量受损通过影响肌肉降解和再生而导致肥胖症的肌肉萎缩
DOI：
10.1016/j.bbrc.2020.02.110
复制
发表时间：
2020-04-30
影响因子：
3.1
通讯作者：
Xiao, Qian
中科院分区：
文献类型：
--
作者：
Fan, Zhen;Xiao, Qian
蛋白水解活性增加与骨骼肌萎缩广泛相关。然而，升高的蛋白水解对于维持细胞内稳态也是至关重要的。本研究旨在探讨自噬在肥胖性肌肉萎缩中的意义，并阐明其机制。首先，高脂饮食（HFD）喂养的大鼠给予载体或氯喹（CQ），一种自噬抑制剂，我们发现，HFD抑制自噬通量，减少大鼠肌纤维的大小和功能。此外，在喂食HFD的大鼠中，MyoD的表达水平降低，而Atrogin-1的表达水平升高。CQ持续抑制自噬加剧了HFD诱导的肌肉损伤以及Atrogin-1和MyoD表达的变化。类似的效果在体外肌管，表现出增加的自噬相关蛋白的水平，但由此产生的自噬通量减少后，暴露于棕榈酸（PA）条件培养基。此外，PA显着降低MyoD水平和诱导Atrogin-1的表达，导致进行性肌管萎缩; CQ加剧了这种现象，但自噬激活剂雷帕霉素缓解。总之，这些在体内和体外的研究结果表明，自噬通量在高脂个体的骨骼肌中被阻断，自噬通过影响肌肉降解和再生介导高脂诱导的肌肉萎缩。(C)2020爱思唯尔公司All rights reserved.
Increased proteolytic activity has been widely associated with skeletal muscle atrophy. However, elevated proteolysis is also critical for the maintenance of intracellular homeostasis. In this study, we aimed to investigate the significance of autophagy in obesity-induced muscle atrophy and clarify the mechanism involved. First, high-fat diet (HFD)-fed rats were administered vehicle or chloroquine (CQ), an autophagy inhibitor, and we found that HFD inhibited autophagic flux and reduced myofiber size and function in rats. Additionally, the expression levels of MyoD were decreased whereas those of Atrogin-1 were increased in rats fed a HFD. Sustained autophagy inhibition by CQ exacerbated HFD-induced muscular damage and changes in the expression of Atrogin-1 and MyoD. Similar effects were reproduced in vitro in myotubes, which exhibited increased levels of autophagy-related proteins, but the resultant autophagic flux was reduced following exposure to palmitic acid (PA)-conditioned medium. Moreover, PA significantly decreased MyoD levels and induced Atrogin-1 expression, leading to progressive myotube atrophy; this phenomenon was aggravated by CQ but alleviated by the autophagy activator rapamycin. Taken together, these in vivo and in vitro findings suggest that autophagic flux is blocked in skeletal muscle of individuals with high lipid, and autophagy mediates high lipid-induced muscle atrophy by affecting muscle degradation and regeneration. (C) 2020 Elsevier Inc. All rights reserved.