Salutary effect of aurintricarboxylic acid on endotoxin- and sepsis-induced changes in muscle protein synthesis and inflammation

• Published in: Shock (Augusta, Ga.) Vol. 41; no. 5; pp. 420 - 428
• Main Authors: Laufenberg, Lacee J, Kazi, Abid A, Lang, Charles H
• Format: Journal Article
• Language: English
• Published: United States 01-05-2014
• Subjects: Animals; Aurintricarboxylic Acid - therapeutic use; Blotting, Western; Cell Line; Inflammation - chemically induced; Inflammation - drug therapy; Lipopolysaccharides - toxicity; Male; Mice; Mice, Inbred C57BL; Muscle Proteins - biosynthesis; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Sepsis - drug therapy; Sepsis - immunology
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/SHK.0000000000000128

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.