Autophagic flux and oxidative capacity of skeletal muscles during acute starvation
Autophagic flux and oxidative capacity of skeletal muscles during acute starvation
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DOI：
10.4161/auto.25955
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发表时间：
2013-10-01
期刊：
影响因子：
13.3
通讯作者：
Hussain, Sabah N. A.
中科院分区：
文献类型：
--
作者：
Mofarrahi, Mahroo;Guo, Yeting;Hussain, Sabah N. A.
自噬是骨骼肌中重要的蛋白水解途径。肌纤维类型组成和氧化能力在自噬中的作用尚不清楚。膈肌（DIA）是一种高氧化能力的快肌纤维，胫骨前肌（TA）是一种低氧化能力的快肌纤维，比目鱼肌（SOL）是一种高氧化能力的慢肌纤维。我们假设氧化能力是骨骼肌自噬的主要决定因素。在成年C57/Bl6小鼠急性（24小时）饥饿后，评估每块肌肉的自噬情况，并与对照组进行比较。自噬通过监测自噬通量，分别注射胰肽（20mg /kg）或秋水仙碱（0.4 mg/kg/天）。通过监测柠檬酸合酶活性来测定氧化能力。在对照小鼠中，TA的自噬通量值明显大于DIA和SOL。在急性饥饿小鼠中，自噬通量增加，在TA中最明显，并且几个关键的自噬相关基因被显著诱导。在对照组和饥饿小鼠中，自噬通量与柠檬酸合酶活性呈负线性相关。饥饿显著诱导AMPK磷酸化，抑制AKT和RPS6KB1磷酸化，同样在TA中最为显著。饥饿诱导Foxo1、Foxo3和Foxo4的表达，并减弱其基因产物的磷酸化。我们得出结论，与氧化能力高的骨骼肌相比，氧化能力低的骨骼肌中基础和饥饿诱导的自噬通量都更大，这种差异是通过选择性激活AMPK途径和抑制AKT-MTOR途径介导的。
Autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type composition and oxidative capacity remain unknown in relation to autophagy. The diaphragm (DIA) is a fast-twitch muscle fiber with high oxidative capacity, the tibialis anterior (TA) muscle is a fast-twitch muscle fiber with low oxidative capacity, and the soleus muscle (SOL) is a slow-twitch muscle with high oxidative capacity. We hypothesized that oxidative capacity is a major determinant of autophagy in skeletal muscles. Following acute (24 h) starvation of adult C57/Bl6 mice, each muscle was assessed for autophagy and compared with controls. Autophagy was measured by monitoring autophagic flux following leupeptin (20 mg/kg) or colchicine (0.4 mg/kg/day) injection. Oxidative capacity was measured by monitoring citrate synthase activity. In control mice, autophagic flux values were significantly greater in the TA than in the DIA and SOL. In acutely starved mice, autophagic flux increased, most markedly in the TA, and several key autophagy-related genes were significantly induced. In both control and starved mice, there was a negative linear correlation of autophagic flux with citrate synthase activity. Starvation significantly induced AMPK phosphorylation and inhibited AKT and RPS6KB1 phosphorylation, again most markedly in the TA. Starvation induced Foxo1, Foxo3, and Foxo4 expression and attenuated the phosphorylation of their gene products. We conclude that both basal and starvation-induced autophagic flux are greater in skeletal muscles with low oxidative capacity as compared with those with high oxidative capacity and that this difference is mediated through selective activation of the AMPK pathway and inhibition of the AKT-MTOR pathways.