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: Hannah Crossland, Dumitru Constantin-Teodosiu, Paul L Greenhaff, Sheila M Gardiner
• Journal: The Journal of physiology (J Physiol) Vol. 588 Issue Pt 8 Pg. 1333-47 (Apr 15 2010) ISSN: 1469-7793 [Electronic] England
• PMID: 20176631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Transcription Factors
• Glucocorticoids
• Interleukin-6
• Lipopolysaccharides
• Muscle Proteins
• Nerve Tissue Proteins
• Tumor Necrosis Factor-alpha
• Foxo1 protein, rat
• Dexamethasone
• Protein Kinases
• pyruvate dehydrogenase kinase 4
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Carbohydrate Metabolism (drug effects, physiology)
• Dexamethasone (pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endotoxemia (chemically induced, complications, metabolism)
• Forkhead Transcription Factors (metabolism)
• Glucocorticoids (pharmacology, therapeutic use)
• Interleukin-6 (metabolism)
• Lipopolysaccharides (adverse effects)
• Male
• Muscle Proteins (drug effects, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Nerve Tissue Proteins (metabolism)
• Oxidation-Reduction
• Protein Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Tumor Necrosis Factor-alpha (metabolism)
• Wasting Syndrome (metabolism, prevention & control)