A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle
Sepsis causes muscle atrophy and insulin resistance, but the underlying mechanisms are unclear. Therefore, the present study examined the effects of lipopolysaccharide (LPS)-induced endotoxaemia on the expression of Akt, Forkhead Box O (FOXO) and its downstream targets, to identify any associations...
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Veröffentlicht in: | The Journal of physiology 2008-11, Vol.586 (22), p.5589-5600 |
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Zusammenfassung: | Sepsis causes muscle atrophy and insulin resistance, but the underlying mechanisms are unclear. Therefore, the present study
examined the effects of lipopolysaccharide (LPS)-induced endotoxaemia on the expression of Akt, Forkhead Box O (FOXO) and
its downstream targets, to identify any associations between changes in FOXO-dependent processes influencing muscle atrophy
and insulin resistance during sepsis. Chronically instrumented male SpragueâDawley rats received a continuous intravenous
infusion of LPS (15 μg kg â1 h â1 ) or saline for 24 h at 0.4 ml h â1 . Animals were terminally anaesthetized and the extensor digitorum longus muscles from both hindlimbs were removed and snap-frozen.
Measurements were made of mRNA and protein expression of selected signalling molecules associated with pathways regulating
protein synthesis and degradation and carbohydrate metabolism. LPS infusion induced increases in muscle tumour necrosis factor-α
(8.9-fold, P < 0.001) and interleukin-6 (8.4-fold, P < 0.01), paralleled by reduced insulin receptor substrate-1 mRNA expression (â0.7-fold, P < 0.01), and decreased Akt1 protein and cytosolic FOXO1 and FOXO3 phosphorylation. These changes were accompanied by significant
increases in muscle atrophy F-box mRNA (5.5-fold, P < 0.001) and protein (2-fold, P < 0.05) expression, and pyruvate dehydrogenase kinase 4 mRNA (15-fold, P < 0.001) and protein (1.6-fold, P < 0.05) expression. There was a 29% reduction in the muscle protein: DNA ratio, a 56% reduction in pyruvate dehydrogenase
complex (PDC) activity ( P < 0.05), and increased glycogen degradation and lactate accumulation. The findings of this study suggest a potential role
for Akt/FOXO in the simultaneous impairment of carbohydrate oxidation, at the level of PDC, and up-regulation of muscle protein
degradation, in LPS-induced endotoxaemia. |
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ISSN: | 0022-3751 1469-7793 |
DOI: | 10.1113/jphysiol.2008.160150 |