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 insulin-like growth factor (IGF)-I receptor and AKT signaling, for its ability to ameliorate the protein metabolic effects of endotoxin (LPS) + interferon (IFN)γ in C2C12 myotubes and sepsis in skeletal muscle. ATA dose- and time-dependently increases mTOR-dependent protein synthesis. Pretreatment with ATA prevents the LPS/IFNγ-induced decrease in protein synthesis at least in part by maintaining mTOR kinase activity, while post-treatment with ATA is able to increase protein synthesis when added up to 6 h after LPS/IFNγ. ATA 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/IFNγ-increase in proteolysis, and the latter change is associated reduced atrogin-1 and MuRF1 mRNA. The ability of ATA to antagonize LPS/IFNγ-induced changes in protein metabolism were associated with its ability to prevent the increases in IL-6 and NOS2 and decreases in IGF-I. 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.

Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer

“…This compound -which has the propensity to polymerization in aqueous solution, forming a stable free radical that has been shown to inhibit various protein-nucleic acid interactions -has previously been shown to possess a number of pharmacological activities, including protease inhibition, complement inhibition, ribonuclease inhibition and neuraminidase inhibition [56][57][58][59][60]. It has also been shown to stimulate insulin-like growth factor 1 receptor, AKT and ERK signaling [61][62][63]. The stimulation of cell proliferation by aurintricarboxylic acid observed in our experiments -similar to previously observed stimulation of cell proliferation of various cell lines by this compound [64][65][66] may be related to the ability of the compound to stimulate var- ious proliferative signaling pathways; we hypothesize that these actions are more predominant in HCT116 cells that any antiproliferative effects that would be expected via CBS inhibition.…”

“…The stimulation of cell proliferation by aurintricarboxylic acid observed in our experiments -similar to previously observed stimulation of cell proliferation of various cell lines by this compound [64][65][66] may be related to the ability of the compound to stimulate var- ious proliferative signaling pathways; we hypothesize that these actions are more predominant in HCT116 cells that any antiproliferative effects that would be expected via CBS inhibition. Although its mode of action and its diverse pharmacological effects suggest lack of specificity (and perhaps lack of in vivo utility) surprisingly, aurintricarboxylic acid is tolerated in experimental animals, and, in fact, has been shown to produce therapeutic benefits in a variety of conditions including encephalitis and sepsis [62,63].…”

High Dietary Selenium Intake Alters Lipid Metabolism and Protein Synthesis in Liver and Muscle of Pigs

“…However, to the best of our knowledge, there was no information on effects of dietary selenium, in particular high selenium intake, on body protein metabolism, although protein synthesis was reported to negatively regulate insulin sensitivity (20,21) and a high protein diet inhibited the development of type 2 diabetes (22). Mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (P70), ribosomal protein S6 (S6), factor 4E binding protein 1 (4EBP1), and eukaryotic translation initiation factor 4E (EIF4E) are key factors involved in the protein synthesis pathway (23)(24)(25)(26)(27). Furthermore, AMP-activated protein kinase (AMPK) plays a key role in regulating energy metabolism (28) and showed a negative association with selenium intake in rats (29).…”

Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion

“…In this work we have used ATA to inhibit the function of PMCA4. The feasibility of ATA as a clinical treatment has yet to be tested, but pre-clinical studies in animal models have revealed potential clinical applications in the treatment of cardiac hypertrophy [27], experimental autoimmune encephalomyelitis [43], sepsis [22], and myocardial ischaemia-reperfusion injury [44].…”