Amino acids, independent of insulin, attenuate skeletal muscle autophagy in neonatal pigs during endotoxemia

Authors: HERNANDEZ-GARCIA, ADRIANA - Children'S Nutrition Research Center (CNRC); MANJARIN, RODRIGO - Children'S Nutrition Research Center (CNRC); SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC); NGUYEN, HANH - Children'S Nutrition Research Center (CNRC); DAVIS, TERESA - Children'S Nutrition Research Center (CNRC); ORELLANA, RENAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Pediatric Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/28/2016
Publication Date: 5/25/2016
Citation: Hernandez-Garcia, A., Manjarin, R., Suryawan, A., Nguyen, H.V., Davis, T.A., Orellana, R.A. 2016. Amino acids, independent of insulin, attenuate skeletal muscle autophagy in neonatal pigs during endotoxemia. Pediatric Research. 80:448–451. doi:10.1038/pr.2016.83.

Interpretive Summary: During sepsis, which is a serious inflammatory response to infection, the synthesis of muscle protein is reduced and the degradation of muscle protein is increased to deliver amino acids to support the inflammatory response. Scientists at the Children's Nutrition Research Center in Houston Texas are developing strategies to prevent the loss of muscle mass during sepsis in pediatric patients. We showed that the intracellular autophagy pathway that regulates protein degradation is stimulated in muscle of a neonatal piglet model during sepsis. However, this protein degradation pathway is suppressed by provision of amino acids. These results support the provision of sufficient amino acids in the nutritional management of infants and children to support the maintenance and growth of muscle mass.

Technical Abstract: Sepsis induces loss of skeletal muscle mass by activating the ubiquitin proteasome (UPS) and autophagy systems. Although muscle protein synthesis in healthy neonatal piglets is responsive to amino acids (AA) stimulation, it is not known if AA can prevent the activation of muscle protein degradation induced by sepsis. We hypothesize that AA attenuate the sepsis-induced activation of UPS and autophagy in neonates. Newborn pigs were infused for 8'h with liposaccharide (LPS) (0 and 10 ug/kg-1/h-1), while circulating glucose and insulin were maintained at fasting levels; circulating AA were clamped at fasting or fed levels. Markers of protein degradation and AA transporters in longissimus dorsi (LD) were examined. Fasting AA increased muscle microtubule-associated protein light 1 chain 3 II (LC3-II) abundance in LPS compared to control, while fed AA levels decreased LC3-II abundance in both LPS and controls. There was no effect of AA supplementation on activated protein kinase (AMP), forkhead box O1 and O4 phosphorylation, nor on sodium-coupled neutral AA transporter 2 and light chain AA transporter 1, muscle RING-finger protein-1 and muscle Atrophy F-Box/Atrogin-1 abundance. These findings suggest that supplementation of AA antagonize autophagy signal activation in skeletal muscle of neonates during endotoxemia.