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

@article{citeulike:3448487, abstract = {Sepsis causes muscle atrophy and insulin resistance, but the mechanisms underlying them 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 microg(.)kg(-1.)h(-1)) or saline for 24 h at 0.4 ml(.)h(-1). Animals were terminally anaesthetised and the extensor digitorum longus muscles from both hindlimbs were removed and snap-frozen. Measurements of mRNA and protein expression of selected signalling molecules associated with pathways regulating protein synthesis and degradation and carbohydrate metabolism were made. LPS infusion induced increases in muscle tumour necrosis factor-alpha (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.}, author = {Crossland, Hannah and Constantin-Teodosiu, Dumitru and Gardiner, Sheila M M. and Constantin, Despina and Greenhaff, Paul L L.}, citeulike-article-id = {3448487}, citeulike-linkout-0 = {http://dx.doi.org/10.1113/jphysiol.2008.160150}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18818241}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18818241}, day = {25}, doi = {10.1113/jphysiol.2008.160150}, issn = {1469-7793}, journal = {The Journal of physiology}, keywords = {aktfoxo, carbohydrate\_oxidation, protein\_loss}, month = {September}, posted-at = {2008-10-24 18:22:47}, priority = {3}, title = {A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle.}, url = {http://dx.doi.org/10.1113/jphysiol.2008.160150}, year = {2008} }

TY - JOUR ID - citeulike:3448487 L3 - citeulike-article-id:3448487 N2 - Sepsis causes muscle atrophy and insulin resistance, but the mechanisms underlying them 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 microg(.)kg(-1.)h(-1)) or saline for 24 h at 0.4 ml(.)h(-1). Animals were terminally anaesthetised and the extensor digitorum longus muscles from both hindlimbs were removed and snap-frozen. Measurements of mRNA and protein expression of selected signalling molecules associated with pathways regulating protein synthesis and degradation and carbohydrate metabolism were made. LPS infusion induced increases in muscle tumour necrosis factor-alpha (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. JF - The Journal of physiology SN - 1469-7793 TI - A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle. KW - aktfoxo KW - carbohydrate_oxidation KW - protein_loss AU - Crossland, Hannah AU - Constantin-Teodosiu, Dumitru AU - Gardiner, Sheila M AU - Constantin, Despina AU - Greenhaff, Paul L PY - 2008/09/25/ UR - http://dx.doi.org/10.1113/jphysiol.2008.160150 ER -