Department of Critical Care Medicine; McGill University Health Centre and Meakins-Christie Laboratories; Department of Medicine; McGill University; Montréal, Québec, Canada.
Division of Pulmonary and Critical Care Medicine; Department of Medicine; Brigham and Women's Hospital; Boston, MA USA.
Autophagy. 2013 Oct;9(10):1604-20. doi: 10.4161/auto.25955. Epub 2013 Aug 15.
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.
自噬是骨骼肌中一种重要的蛋白水解途径。肌肉纤维类型组成和氧化能力与自噬的关系尚不清楚。膈肌（DIA）是一种具有高氧化能力的快肌纤维，比目鱼肌（TA）是一种具有低氧化能力的快肌纤维，而跖肌（SOL）是一种具有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，评估每种肌肉的自噬情况，并与对照组进行比较。自噬通过监测亮抑酶肽（20mg/kg）或秋水仙碱（0.4mg/kg/天）注射后的自噬通量来测量。氧化能力通过监测柠檬酸合酶活性来测量。在对照组小鼠中，TA 中的自噬通量值明显高于 DIA 和 SOL。在急性饥饿的小鼠中，自噬通量增加，在 TA 中最为明显，并且几个关键的自噬相关基因明显被诱导。在对照组和饥饿组小鼠中，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，并抑制 AKT 和 RPS6KB1 磷酸化，在 TA 中最为明显。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，与具有高氧化能力的骨骼肌相比，低氧化能力的骨骼肌的基础和饥饿诱导的自噬通量更大，这种差异是通过选择性激活 AMPK 途径和抑制 AKT-MTOR 途径来介导的。
