title: Low-dose dexamethasone prevents endotoxaemia-induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle.
abstract: We recently provided evidence suggesting a role for cytokine-mediated inhibition of Akt/Forkhead box O 1 (FOXO1) signalling in the induction of muscle atrophy and impairment of muscle carbohydrate oxidation during lipopolysaccharide (LPS)-induced endotoxaemia in rats. We hypothesized that a low-dose dexamethasone (Dex; anti-inflammatory agent) infusion during endotoxaemia would prevent the LPS-induced impairment of Akt/FOXO1 signalling, and therefore prevent the muscle atrophy and impairment of carbohydrate oxidation. Chronically instrumented Sprague-Dawley rats received a continuous intravenous infusion of LPS (15 microg kg(-1) h(-1)), Dex (12.5 microg kg(-1) h(-1)), Dex+LPS or saline for 24 h at 0.4 ml h(-1). LPS infusion caused haemodynamic changes consistent with a hyperdynamic circulation and induced increases in muscle tumour necrosis factor-alpha (TNF-alpha; 10-fold, P < 0.001), interleukin-6 (IL-6; 14-fold, P < 0.001) and metallothionein-1A (MT-1A; 187-fold, P < 0.001) mRNA expression. Dex co-administration abolished most of the haemodynamic effects of LPS and reduced the increase in muscle TNF-alpha, IL-6 and MT-1A by 51% (P < 0.01), 85% (P < 0.001) and 58% (P < 0.01), respectively. Dex infusion during endotoxaemia also prevented the LPS-induced 40% reduction in the muscle protein:DNA ratio and decrease in Akt phosphorylation, and partially prevented the reduction in FOXO1 phosphorylation. However, Dex did not prevent the LPS-mediated increase in muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) mRNA expression, but did significantly reduce the LPS-mediated increase in cathepsin-L mRNA expression and enzyme activity by 43% (P < 0.001) and 53% (P < 0.05), respectively. Furthermore, Dex suppressed LPS-induced pyruvate dehydrogenase kinase 4 (PDK4) mRNA upregulation by approximately 50% (P < 0.01), and prevented LPS-mediated muscle glycogen breakdown and lactate accumulation. Thus, low-dose Dex infusion during endotoxaemia prevented muscle atrophy and the impairment of carbohydrate oxidation, potentially through suppression of cytokine-mediated Akt/FOXO inhibition, and blunting of cathepsin-L-mediated lysosomal protein breakdown.
authors.affiliation: Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. mbxhc@nottingham.ac.uk
authors.forename: Hannah
authors.initials: H
authors.lastname: Crossland
authors.forename: Dumitru
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Gardiner
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019282:Wasting Syndrome / Q000378:metabolism / Q000517:prevention & control*; D000071161:Forkhead Box Protein O1
chemical_list: D003907:Dexamethasone; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C403287:pyruvate dehydrogenase kinase 4