Oxidant-induced atrogin-1 and transforming growth factor-beta1 precede alcohol-related myopathy in rats.
Alcohol-related chronic myopathy is characterized by severe biochemical and structural changes to skeletal muscle. Our goals were to: (1) identify early regulatory elements that precede the overt manifestation of plantaris atrophy; and (2) circumvent these derangements by supplementing alcohol-fed rats with the glutathione precursor, procysteine. After 6 weeks of daily ingestion, before the development of overt atrophy of the plantaris muscle, alcohol increased several markers of oxidative stress and increased gene expressions of atrogin-1 and transforming growth factor-beta1 (TGF-beta1) by approximately 60- and approximately 65-fold, respectively, which were attenuated by procysteine supplementation. Interestingly, after 28 weeks of alcohol ingestion, when overt plantaris atrophy had developed, atrogin-1 and TGF-beta1 gene expression had returned to baseline levels. Together, these findings suggest that alcohol-induced, redox-sensitive alterations drive pro-atrophy signaling pathways that precede muscle atrophy. Therefore, targeted anti-oxidant treatments such as procysteine supplementation may benefit individuals with chronic alcohol abuse, particularly if given prior to the development of clinically significant myopathy.
Otis
Jeffrey S
JS
Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, Emory University School of Medicine, Decatur, Georgia 30033, USA. jsotis@emory.edu
Brown
Lou Ann S
LA
Guidot
David M
DM
D000437:Alcoholism / Q000150:complications*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D000431:Ethanol / Q000009:adverse effects; D005978:Glutathione / Q000819:agonists / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D053778:Thiazolidines / Q000494:pharmacology / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D000975:Antioxidants; D015415:Biomarkers; D002492:Central Nervous System Depressants; D009124:Muscle Proteins; D016877:Oxidants; D012333:RNA, Messenger; D053778:Thiazolidines; D053773:Transforming Growth Factor beta1; D000431:Ethanol; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid