A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle

• Published in: The Journal of physiology Vol. 586; no. 22; pp. 5589 - 5600
• Main Authors: Crossland, Hannah, Constantin‐Teodosiu, Dumitru, Gardiner, Sheila M., Constantin, Despina, Greenhaff, Paul L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15.11.2008; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Animals; Carbohydrate Metabolism; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Insulin Resistance - genetics; Insulin Resistance - physiology; Integrative; Male; Models, Biological; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscular Atrophy - etiology; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oxidation-Reduction; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sepsis - complications; Sepsis - genetics; Sepsis - metabolism; Signal Transduction; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2008.160150

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 Sprague–Dawley rats received a continuous intravenous infusion of LPS (15 μg kg −1 h −1 ) or saline for 24 h at 0.4 ml h −1 . 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 (−0.7-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.