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Title: Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia

Author
item HERNANDEZ-GARCIA, ADRIAN - Children'S Nutrition Research Center (CNRC)
item COLUMBUS, DANIEL - Children'S Nutrition Research Center (CNRC)
item MANJARIN, RODRIGO - Children'S Nutrition Research Center (CNRC)
item NGUYEN, HANH - Children'S Nutrition Research Center (CNRC)
item SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC)
item ORELLANA, RENÁN - Children'S Nutrition Research Center (CNRC)
item DAVIS, TERESA - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/6/2016
Publication Date: 9/13/2016
Citation: Hernandez-Garcia, A.D., Columbus, D.A., Manjarin, R., Nguyen, H.V., Suryawan, A., Orellana, R.A., Davis, T.A. 2016. Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia. American Journal of Physiology - Endocrinology and Metabolism. 311(4):E791-E801.

Interpretive Summary: Endotoxemia, a condition characterized by the presence of endotoxins in the blood, can cause muscle breakdown. In previous studies we show that leucine, an amino acid, stimulates muscle protein synthesis in healthy newborn pigs. In this study we determine the effect of leucine on muscle protein synthesis in newborn pigs during acute endotoxemia. Acute endotoxemia was induced by infusing newborn pigs with lipopolysaccharide, bacterial cell walls, for 8 hours. During acute endotoxemia, leucine was infused to the animals while plasma amino acids, glucose, and insulin were maintained at fasting levels. Muscle protein synthesis and the activation of signaling cascades for protein synthesis and protein breakdown were analyzed. The results showed that leucine increased protein synthesis in several skeletal muscle types. The leucine-induced muscle protein synthesis mainly was due to increased activation of signaling cascades of protein synthesis and decreased activation of signaling cascades for protein breakdown. The results suggest that administration of leucine during acute endotoxemia can be helpful to alleviate muscle breakdown by increasing muscle protein synthesis. Thus, in the hospital setting, leucine may be used to preserve muscle mass of newborn babies who have acute endotoxemia.

Technical Abstract: Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation (PD) signaling in neonatal muscle during endotoxemia, overnight-fasted neonatal pigs were infused for 8 h with LPS or saline while plasma amino acids, glucose, and insulin were maintained at fasting levels during pancreatic-substrate clamps. Leu or saline was infused during the last hour. Markers of PS and PD were determined in skeletal muscle. Compared with controls, Leu increased PS in longissimus dorsi (LD), gastrocnemius, and soleus muscles. LPS decreased PS in these three muscles by 36%, 28%, and 38%, but Leu antagonized that reduction by increasing PS by 84%, 81%, and 83%, respectively, when supplemented to LPS. Leu increased eukaryotic translation initiation factor (eIF)3b-raptor interactions, eIF4E-binding protein-1, and S6 kinase 1 phosphorylation as well as eIF4E·eIF4G complex formation in LD, gastrocnemius, and soleus muscles of control and LPS-treated pigs. In LD muscle, LPS increased the light chain (LC)3-II-to-LC3 ratio and muscle-specific RING finger (MuRF-1) abundance but not atrogin-1 abundance or AMP-activated protein kinase-a phosphorylation. Leu supplementation to LPS-treated pigs reduced the LC3-II-to-LC3 ratio, MuRF-1 abundance, and AMP-activated protein kinase-a phosphorylation compared with LPS alone. In conclusion, parenteral Leu supplementation attenuates the LPS-induced reduction in PS by stimulating mammalian target of rapamycin complex 1-dependent translation and may reduce PD by attenuating autophagy-lysosome and MuRF-1 signaling in neonatal skeletal muscle.