title: Amino acid supplementation is anabolic during the acute phase of endotoxin-induced inflammation: A human randomized crossover trial.
abstract: OBJECTIVE
  Inflammation is catabolic and causes muscle loss. It is unknown if amino acid supplementation reverses these effects during the acute phase of inflammation. The aim was to test whether amino acid supplementation counteracts endotoxin-induced catabolism.
  
  
  METHODS
  Eight young, healthy, lean males were investigated three times in randomized order: (i) normal conditions (Placebo), (ii) endotoxemia (LPS), and (iii) endotoxemia with amino acid supplementation (LPS + A). Protein kinetics were determined using phenylalanine, tyrosine, and urea tracers. Each study day consisted of a four-hour non-insulin stimulated period and a two-hour hyperinsulinemic euglycemic clamp period. Muscle biopsies were collected once each period.
  
  
  RESULTS
  Endotoxin administration created a significant inflammatory response (cytokines, hormones, and vital parameters) without significant differences between LPS and LPS + A. Whole body protein breakdown was elevated during LPS compared with Placebo and LPS + A (p < 0.05). Whole body protein synthesis was higher during LPS + A than both Placebo and LPS (p < 0.003). Furthermore, protein synthesis was higher during LPS than during Placebo (p < 0.02). Net muscle phenylalanine release was markedly decreased during LPS + A (p < 0.004), even though muscle protein synthesis and breakdown rates did not differ significantly between interventions. LPS + A increased mammalian target of rapamycin (mTOR) phosphorylation (p < 0.05) and eukaryotic translation factor 4E-binding protein 1 (4EBP1) phosphorylation (p = 0.007) without activating AMPK or affecting insulin signaling through Akt. During insulin stimulation net muscle phenylalanine release and protein degradation were further reduced.
  
  
  CONCLUSIONS
  Amino acid supplementation in the acute phase of inflammation reduces whole body and muscle protein loss, and this effect is associated with activation of mTOR and downstream signaling to protein synthesis through mTORC1, suggesting a therapeutic role for intravenous amino acids in inflammatory states.
  
  
  BACKGROUND
  The Central Denmark Region Ethics Commitee (1-10-71-410-12) www.clinicaltrials.gov (identification number NCT01705782).
authors.affiliation: Department of Internal Medicine and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark. Electronic address: nikolaj.rittig@clin.au.dk.
authors.forename: N
authors.initials: N
authors.lastname: Rittig
authors.affiliation: Department of Internal Medicine and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Bach
authors.affiliation: Department of Internal Medicine and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
authors.forename: H H
authors.initials: HH
authors.lastname: Thomsen
authors.affiliation: Section for Forensic Chemistry, Department of Forensic Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Johannsen
authors.affiliation: Department of Internal Medicine and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
authors.forename: J O
authors.initials: JO
authors.lastname: Jørgensen
authors.affiliation: Department of Internal Medicine and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Richelsen
authors.affiliation: Department of Internal Medicine and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark; Department of Biochemical Pathology, Institute for Clinical Medicine, Aarhus University Hospital, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Department of Internal Medicine and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Møller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000596:Amino Acids / Q000008:administration & dosage*; D015992:Body Mass Index; D018797:Cell Cycle Proteins; D018592:Cross-Over Studies; D019587:Dietary Supplements; D019446:Endotoxemia / Q000188:drug therapy; D004731:Endotoxins / Q000633:toxicity*; D015309:Glucose Clamp Technique; D006728:Hormones / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016014:Linear Models; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008962:Models, Theoretical; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010649:Phenylalanine / Q000097:blood; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014443:Tyrosine / Q000097:blood; D014508:Urea / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004731:Endotoxins; D006728:Hormones; C508609:IL10 protein, human; C508600:IL6 protein, human; D007328:Insulin; D015850:Interleukin-6; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014443:Tyrosine; D010649:Phenylalanine; D014508:Urea; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Amino acids; Endotoxin (lipopolysaccharide, LPS); Inflammation; Tracer kinetics; mTOR