title: Salutary effect of aurintricarboxylic acid on endotoxin- and sepsis-induced changes in muscle protein synthesis and inflammation.
abstract: Small molecule nonpeptidyl molecules are potentially attractive drug candidates as adjunct therapies in the treatment of sepsis-induced metabolic complications. As such, the current study investigates the use of aurintricarboxylic acid (ATA), which stimulates insulinlike growth factor 1 receptor and AKT signaling, for its ability to ameliorate the protein metabolic effects of endotoxin (lipopolysaccharide [LPS]) + interferon γ (IFN-γ) in C2C12 myotubes and sepsis in skeletal muscle. Aurintricarboxylic acid dose- and time-dependently increases mTOR (mammalian or mechanistic target of rapamycin)-dependent protein synthesis. Pretreatment with ATA prevents the LPS/IFN-γ-induced decrease in protein synthesis at least in part by maintaining mTOR kinase activity, whereas posttreatment with ATA is able to increase protein synthesis when added up to 6 h after LPS/IFN-γ. Aurintricarboxylic acid also reverses the amino acid resistance, which is detected in response to nutrient deprivation. Conversely, ATA decreases the basal rate of protein degradation and prevents the LPS/IFN-γ increase in proteolysis, and the latter change is associated reduced atrogin 1 and MuRF1 mRNA. The ability of ATA to antagonize LPS/IFN-γ-induced changes in protein metabolism was associated with its ability to prevent the increases in interleukin 6 and nitric oxide synthase 2 and decreases in insulinlike growth factor 1. In vivo studies indicate ATA acutely increases skeletal muscle, but not cardiac, protein synthesis and attenuates the loss of lean body mass over 5 days. These data suggest ATA and other small molecule agonists of endogenous anabolic hormones may prove beneficial in treating sepsis by decreasing the inflammatory response and improving muscle protein balance.
authors.affiliation: Departments of Cellular & Molecular Physiology, and Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Lacee J
authors.initials: LJ
authors.lastname: Laufenberg
authors.forename: Abid A
authors.initials: AA
authors.lastname: Kazi
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
mesh_terms: D000818:Animals; D001312:Aurintricarboxylic Acid / Q000627:therapeutic use*; D015153:Blotting, Western; D002460:Cell Line; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D009124:Muscle Proteins; D001312:Aurintricarboxylic Acid