Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia.
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-α phosphorylation. Leu supplementation to LPS-treated pigs reduced the LC3-II-to-LC3 ratio, MuRF-1 abundance, and AMP-activated protein kinase-α 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.
Children's Nutrition Research Center, United States Department of Agriculture/Agricultural Research Service, Houston, Texas; and Critical Care Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Adriana D
AD
Hernandez-García
Children's Nutrition Research Center, United States Department of Agriculture/Agricultural Research Service, Houston, Texas; and.
Daniel A
DA
Columbus
Children's Nutrition Research Center, United States Department of Agriculture/Agricultural Research Service, Houston, Texas; and.
Rodrigo
R
Manjarín
Children's Nutrition Research Center, United States Department of Agriculture/Agricultural Research Service, Houston, Texas; and.
Hanh V
HV
Nguyen
Children's Nutrition Research Center, United States Department of Agriculture/Agricultural Research Service, Houston, Texas; and.
Agus
A
Suryawan
Children's Nutrition Research Center, United States Department of Agriculture/Agricultural Research Service, Houston, Texas; and Critical Care Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Renán A
RA
Orellana
Children's Nutrition Research Center, United States Department of Agriculture/Agricultural Research Service, Houston, Texas; and tdavis@bcm.edu.
Teresa A
0000-0002-4610-9795
TA
Davis
D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000187:drug effects; D019446:Endotoxemia / Q000378:metabolism*; D005260:Female; D007930:Leucine / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D013552:Swine
D008070:Lipopolysaccharides; D009124:Muscle Proteins; D007930:Leucine
autophagy; leucine; protein degradation; protein synthesis; skeletal muscle