title: Chronic binge alcohol administration accentuates expression of pro-fibrotic and inflammatory genes in the skeletal muscle of simian immunodeficiency virus-infected macaques.
abstract: BACKGROUND
  Chronic binge alcohol (CBA) administration exacerbates skeletal muscle (SKM) wasting at the terminal stage of simian immunodeficiency virus (SIV) infection in rhesus macaques. This is associated with a pro-inflammatory and oxidative milieu which we have previously shown to be associated with a disrupted balance between anabolic and catabolic mechanisms. In this study, we attempted to characterize the SKM gene expression signature in CBA-administered SIV-infected macaques, using the same animals from the previous study.
  
  
  METHODS
  Administration of intragastric alcohol or sucrose to male rhesus macaques began 3 months prior to SIV infection and continued throughout the duration of study. Gene transcriptomes of SKM excised at necropsy (~10 months post-SIV) from healthy na\xEFve control (Control), sucrose-administered, SIV-infected (SUC-SIV), and CBA-administered, SIV-infected (CBA-SIV) macaques were evaluated in microarray data sets. The Protein Analysis Through Evolutionary Relationships classification tool was used to filter differentially regulated genes based on their predicted function into select biological processes relevant to SKM wasting which were inflammation, extracellular matrix (ECM) remodeling, and metabolism.
  
  
  RESULTS
  In total, 1,124 genes were differentially regulated between SUC-SIV and Controls, 2,022 genes were differentially expressed between the CBA-SIV and Controls, and 836 genes were differentially expressed between CBA-SIV and SUC-SIV animals. The relevance of altered gene expression was reflected in the up-regulation of pro-inflammatory CCL-2, CCL-8, CX3CL1, SELE, HP, and TNFRS10A mRNA expression. In addition, ECM remodeling was reflected in the up-regulation of TIMP-1, MMP 2, and MMP 9 mRNA expression and transforming growth factor-beta 1 protein expression. In addition, hydroxyproline content and picrosirius staining reflected increased collagen deposition in the CBA-SIV muscle tissue.
  
  
  CONCLUSIONS
  The results of the study demonstrate SKM inflammation as an important underlying mechanism for muscle wasting. In addition, the study provides evidence of SKM fibrotic transformation as a factor in CBA-induced accentuation of SIV-associated muscle wasting.
authors.affiliation: Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Comprehensive Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dodd
authors.forename: Liz
authors.initials: L
authors.lastname: Simon
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: LeCapitaine
authors.forename: Jovanny
authors.initials: J
authors.lastname: Zabaleta
authors.forename: Jason
authors.initials: J
authors.lastname: Mussell
authors.forename: Paul
authors.initials: P
authors.lastname: Berner
authors.forename: Stephen
authors.initials: S
authors.lastname: Ford
authors.forename: Jason
authors.initials: J
authors.lastname: Dufour
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bagby
authors.forename: Steve
authors.initials: S
authors.lastname: Nelson
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Molina
mesh_terms: D000818:Animals; D063425:Binge Drinking / Q000453:epidemiology / Q000378:metabolism*; D002908:Chronic Disease; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D008251:Macaca; D008253:Macaca mulatta; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000453:epidemiology / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus
chemical_list: D018836:Inflammation Mediators; D009124:Muscle Proteins; D000431:Ethanol
keywords: Alcohol; Microarray; Pro-Fibrotic; Simian Immunodeficiency Virus; Skeletal Muscle