title: Involvement of the FoxO1/MuRF1/Atrogin-1 Signaling Pathway in the Oxidative Stress-Induced Atrophy of Cultured Chronic Obstructive Pulmonary Disease Myotubes.
abstract: Oxidative stress is thought to be one of the most important mechanisms implicated in the muscle wasting of chronic obstructive pulmonary disease (COPD) patients, but its role has never been demonstrated. We therefore assessed the effects of both pro-oxidant and antioxidant treatments on the oxidative stress levels and atrophic signaling pathway of cultured COPD myotubes. Treatment of cultured COPD myotubes with the pro-oxidant molecule H2O2 resulted in increased ROS production (P = 0.002) and protein carbonylation (P = 0.050), in association with a more pronounced atrophy of the myotubes, as reflected by a reduced diameter (P = 0.003), and the activated expression of atrophic markers MuRF1 and FoxO1 (P = 0.022 and P = 0.030, respectively). Conversely, the antioxidant molecule ascorbic acid induced a reduction in ROS production (P<0.001) and protein carbonylation (P = 0.019), and an increase in the myotube diameter (P<0.001) to a level similar to the diameter of healthy subject myotubes, in association with decreased expression levels of MuRF1, atrogin-1 and FoxO1 (P<0.001, P = 0.002 and P = 0.042, respectively). A significant negative correlation was observed between the variations in myotube diameter and the variations in the expression of MuRF1 after antioxidant treatment (P = 0.047). Moreover, ascorbic acid was able to prevent the H2O2-induced atrophy of COPD myotubes. Last, the proteasome inhibitor MG132 restored the basal atrophy level of the COPD myotubes and also suppressed the H2O2-induced myotube atrophy. These findings demonstrate for the first time the involvement of oxidative stress in the atrophy of COPD peripheral muscle cells in vitro, via the FoxO1/MuRF1/atrogin-1 signaling pathway of the ubiquitin/proteasome system.
authors.affiliation: PhyMedExp, INSERM U1046, CNRS UMR9214, University of Montpellier, Montpellier, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pomiès
authors.affiliation: PhyMedExp, INSERM U1046, CNRS UMR9214, University of Montpellier, Montpellier, France.|Department of Clinical Physiology, CHRU of Montpellier, Montpellier, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Blaquière
authors.affiliation: PhyMedExp, INSERM U1046, CNRS UMR9214, University of Montpellier, Montpellier, France.|Clinique du Souffle "La Solane", Fontalvie - 5-Santé Group, Osséja, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maury
authors.affiliation: PhyMedExp, INSERM U1046, CNRS UMR9214, University of Montpellier, Montpellier, France.|Department of Clinical Physiology, CHRU of Montpellier, Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mercier
authors.affiliation: PhyMedExp, INSERM U1046, CNRS UMR9214, University of Montpellier, Montpellier, France.|Department of Clinical Physiology, CHRU of Montpellier, Montpellier, France.
authors.forename: Fares
authors.initials: F
authors.lastname: Gouzi
authors.affiliation: PhyMedExp, INSERM U1046, CNRS UMR9214, University of Montpellier, Montpellier, France.|Department of Clinical Physiology, CHRU of Montpellier, Montpellier, France.
authors.forename: Maurice
authors.initials: M
authors.lastname: Hayot
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009124:Muscle Proteins / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000070584:Tripartite Motif Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D000071161:Forkhead Box Protein O1; D007976:Leupeptins; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D006861:Hydrogen Peroxide; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; D001205:Ascorbic Acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde