Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle
Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle
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DOI：
10.1016/j.cellsig.2016.03.005
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发表时间：
2016-06-01
影响因子：
4.8
通讯作者：
Kiens, Bente
中科院分区：
文献类型：
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作者：
Fritzen, Andreas Maechel;Frosig, Christian;Kiens, Bente
在诱导自噬体降解过程期间，LC 3-I脂化为LC 3-II并与货物分离膜缔合，从而允许自噬体形成。LC 3的脂化导致LC 3-II/LC 3-I比率增加，并且该比率是包括骨骼肌在内的各种组织中的自噬的常用标志物。根据细胞研究，AMPK被认为是LC 3脂化的必要和充分条件。本研究的目的是研究AMPK在调节LC 3脂质化中的作用，LC 3脂质化是骨骼肌自噬的标志。我们观察到禁食12小时后AMPK α 2激酶死亡（KD）（p < 0.001）和野生型（WT）（p < 0.05）小鼠骨骼肌中LC 3-II/LC 3-I比率增加，AMPK α 2激酶死亡小鼠中LC 3-II/LC 3-I比率大于野生型小鼠（p < 0.05）。在两种基因型中，禁食诱导的LC 3-II/LC 3-I比率的增加与血浆胰岛素浓度的初始降低（p < 0.01）、肌肉mTORC 1信号传导的随后降低以及自噬促进蛋白FoxO 3a和ULK 1水平的增加（p < 0.05）相一致。此外，与年轻小鼠相比，在老年小鼠中观察到更高（p < 0.01）的LC 3-II/LC 3-I比率。我们不能检测到任何变化，无论是在体内跑步机运动或原位收缩的LC 3脂化。总的来说，这些发现表明AMPK α（2）不是禁食和衰老诱导LC 3脂质化所必需的。此外，在禁食和衰老期间，缺乏功能性AMPK α（2）的肌肉中LC 3脂质化增加。此外，LC 3脂质化似乎不是小鼠肌肉收缩的普遍反应。(C)2016爱思唯尔公司保留所有权利。
During induction of the autophagosomal degradation process, LC3-I is lipidated to LC3-II and associates to the cargo isolation membrane allowing for autophagosome formation. Lipidation of LC3 results in an increased LC3-II/LC3-I ratio, and this ratio is an often used marker for autophagy in various tissues, including skeletal muscle. From cell studies AMPK has been proposed to be necessary and sufficient for LC3 lipidation. The aim of the present study was to investigate the role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle. We observed an increase in the LC3-II/LC3-I ratio in skeletal muscle of AMPK alpha(2) kinase-dead (KD) (p < 0.001) and wild type (WT) (p < 0.05) mice after 12 h of fasting, which was greater (p < 0.05) in AMPK alpha(2) KD mice than in WT. The fasting- induced increase in the LC3-II/LC3-I ratio in both genotypes coincided with an initial decrease (p < 0.01) in plasma insulin concentration, a subsequent decrease in muscle mTORC1 signaling and increased (p < 0.05) levels of the autophagy-promoting proteins, FoxO3a and ULK1. Furthermore, a higher (p < 0.01) LC3-II/LC3-I ratio was observed in old compared to young mice. We were not able to detect any change in LC3 lipidation with either in vivo treadmill exercise or in situ contractions. Collectively, these findings suggest that AMPK alpha(2) is not necessary for induction of LC3 lipidation with fasting and aging. Furthermore, LC3 lipidation is increased in muscle lacking functional AMPK alpha(2) during fasting and aging. Moreover, LC3 lipidation seems not to be a universal response to muscle contraction in mice. (C) 2016 Elsevier Inc All rights reserved.