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 + (IFN-+) in C2C12 myotubes and sepsis in skeletal muscle. Aurintricarboxylic acid dose-and time-dependently increases mTOR (mammalian or mechanistic target of rapamycin)Ydependent protein synthesis. Pretreatment with ATA prevents the LPS/IFN-+Yinduced 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-+. 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-+ increase in proteolysis, and the latter change is associated reduced atrogin 1 and MuRF1 mRNA. The ability of ATA to antagonize LPS/IFN-+Yinduced 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.
All Science Journal Classification (ASJC) codes
- Emergency Medicine
- Critical Care and Intensive Care Medicine