p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting.
Oxidative stress is a primary trigger of cachectic muscle wasting, but the signaling pathway(s) that links it to the muscle wasting processes remains to be defined. Here, we report that activation of p38 mitogen-activated protein kinase (MAPK) (phosphorylation) and increased oxidative stress (trans-4-hydroxy-2-nonenal protein modification) in skeletal muscle occur as early as 8 h after lipopolysaccharide (1 mg/kg) and 24 h after dexamethasone (25 mg/kg) injection (intraperitoneal) in mice, concurrent with upregulation of autophagy-related genes, Atg6, Atg7, and Atg12. Treating cultured C2C12 myotubes with oxidant hydrogen peroxide (4 h) resulted in increased p38 phosphorylation and reduced FoxO3 phosphorylation along with induced Atg7 mRNA expression without activation of NF-kappaB or FoxO3a transcriptional activities. Furthermore, inhibition of p38alpha/beta by SB202190 blocked hydrogen peroxide-induced atrophy with diminished upregulation of Atg7 and atrogenes [muscle atrophy F-box protein (MAFbx/Atrogin-1), muscle ring finger protein 1 (MuRF-1), and Nedd4]. These findings provide direct evidence for p38alpha/beta MAPK in mediating oxidative stress-induced autophagy-related genes, suggesting that p38alpha/beta MAPK regulates both the ubiquitin-proteasome and the autophagy-lysosome systems in muscle wasting.
McClung
J M
JM
Exercise Biochemistry Laboratory, University of Florida, Gainesville, Florida, USA. joseph.mcclung@duke.edu
Judge
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Powers
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Yan
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D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D002100:Cachexia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D003907:Dexamethasone; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006019:Glycolysis; D006861:Hydrogen Peroxide / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D054875:Ubiquitination
D000447:Aldehydes; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007093:Imidazoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole