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Low‐dose dexamethasone prevents endotoxaemia‐induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle
Author(s) -
Crossland Hannah,
ConstantinTeodosiu Dumitru,
Greenhaff Paul L.,
Gardiner Sheila M.
Publication year - 2010
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.183699
Subject(s) - endocrinology , medicine , skeletal muscle , foxo1 , muscle atrophy , dexamethasone , protein kinase b , atrophy , tumor necrosis factor alpha , chemistry , phosphorylation , biology , biochemistry
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 μg kg −1 h −1 ), Dex (12.5 μg 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‐α (TNF‐α; 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‐α, 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 ∼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.