Amino acid supplementation is anabolic during the acute phase of endotoxin-induced inflammation: A human randomized crossover trial.
BACKGROUND & AIMS
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.


CLINICAL TRIAL REGISTRY
The Central Denmark Region Ethics Commitee (1-10-71-410-12) www.clinicaltrials.gov (identification number NCT01705782).
['Rittig|N|N|', 'Bach|E|E|', 'Thomsen|H H|HH|', 'Johannsen|M|M|', 'Jørgensen|J O|JO|', 'Richelsen|B|B|', 'Jessen|N|N|', 'Møller|N|N|']
D048868:Adaptor Proteins, Signal Transducing D000328:Adult D000596:Amino Acids D015992:Body Mass Index D018797:Cell Cycle Proteins D018592:Cross-Over Studies D019587:Dietary Supplements D019446:Endotoxemia D004731:Endotoxins D015309:Glucose Clamp Technique D006728:Hormones D006801:Humans D007249:Inflammation D007328:Insulin D016753:Interleukin-10 D015850:Interleukin-6 D016014:Linear Models D008297:Male D000076222:Mechanistic Target of Rapamycin Complex 1 D008962:Models, Theoretical D046912:Multiprotein Complexes D018482:Muscle, Skeletal D010649:Phenylalanine D010750:Phosphoproteins D010766:Phosphorylation D014176:Protein Biosynthesis D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases D014409:Tumor Necrosis Factor-alpha D014443:Tyrosine D014508:Urea
Amino acids Inflammation mTOR Endotoxin (lipopolysaccharide, LPS) Tracer kinetics