Insulin Antagonizes SIRT1 and NF‐κB Signaling in Skeletal Muscle of Neonatal Pigs during Chronic Infection

Intracellular SIRT1and NF‐κB are increased in sepsis, and associated with increased muscle protein degradation via activation of FOXO1 and MuRF1. Although sepsis‐induced muscle protein catabolism can be ameliorated by insulin in neonatal pigs, the effect of insulin on SIRT1 and NF‐κB activation is not known. We hypothesize that insulin will antagonize SIRT1 and NF‐κB expression induced by chronic infection in neonatal muscle. Sixteen 2‐d‐old pigs underwent cecal ligation and puncture (CLP) or sham surgery (CON) and were pair‐gavage fed for 5 d. Pancreatic‐substrate clamps were performed for 2 h providing insulin to attain fasting or re‐fed levels and to maintain glucose and AA in the fasting range. Expression of SIRT1, NF‐κB and degradation signal activation was measured in longissimus dorsi (LD) muscle. Insulin decreased circulating glutamine, arginine and citrulline in CLP. In LD, CLP increased NF‐κB abundance and correlated positively with that of MuRF1, while insulin lowered SIRT1 abundance in both CLP and CON, decreased MuRF1 and increased FOXO1 phosphorylation in CLP but not in CON. FOXO1 phosphorylation negatively correlated with SIRT1 abundance. These findings suggest that in chronic survival models of neonatal peritonitis, insulin antagonizes the catabolic effect of SIRT1 and NF‐κB in skeletal muscle. NIH AR44474, NIH AR51563 and USDA/ARS 6250‐51000‐055.