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Antioxid Redox Signal. 2014 Jan 20;20(3):443-59. doi: 10.1089/ars.2013.5410.

Reactive oxygen species regulation of autophagy in skeletal muscles.

Author information

1
1 Department of Critical Care, McGill University Health Centre and Meakins-Christie Laboratories , Montréal, Canada .

Abstract

OBJECTIVE:

To evaluate the effects of physiological levels of mitochondrial-derived reactive oxygen species (ROS) on skeletal muscle autophagy, a proteolytic pathway designed to regulate contractile and myofilament homeostasis and to recycle long-lived proteins and damaged organelles.

RESULTS:

Basal levels of autophagy and autophagy triggered by 1.5 to 4 h of acute nutrient deprivation, rapamycin treatment, or leucine deprivation were measured in differentiated C2C12 myotubes using long-lived protein degradation assays, LC3B lipidation, autophagy-related gene expression, and electron microscopy. Preincubation with the general antioxidants tempol (superoxide dismutase mimic) and N-acetyl cysteine (NAC) or the mitochondria-specific antioxidants mito-tempol and SS31 significantly decreased the rates of long-lived protein degradation and LC3B flux and blocked the induction of autophagy-related gene expression. Mitochondrial ROS levels significantly increased in response to acute nutrient deprivation and rapamycin treatment. Mito-tempol and tempol blocked this response. Antioxidants decreased AMP-activated protein kinase (AMPK) phosphorylation by 40% and significantly increased protein kinase B (AKT) phosphorylation, but exerted no effects on mTORC1-dependent ULK1 phosphorylation on Ser(555). NAC significantly decreased basal LC3B autophagic flux in skeletal muscles of mice.

INNOVATION:

We report for the first time that endogenous ROS promote skeletal muscle autophagy at the basal level and in response to acute nutrient starvation and mTORC1 inhibition. We also report for the first time that mitochondrial-derived ROS promote skeletal muscle autophagy and that this effect is mediated, in part, through regulation of autophagosome initiation and AKT inhibition.

CONCLUSION:

Mitochondrial-derived ROS promote skeletal muscle autophagy and this effect is mediated, in part, through activation of AMPK and inhibition of AKT.

PMID:
24180497
DOI:
10.1089/ars.2013.5410
[Indexed for MEDLINE]

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