Glucocorticoid-induced insulin resistance of protein synthesis is independent of the rapamycin-sensitive pathways in rat skeletal muscle

Abstract

This study was designed to evaluate the role of p70 S6 kinase (p70 S6K ), p90 S6 kinase (p90 RSK ) and mitogenactivated protein (MAP) kinase pathways in the insulin resistance of muscle protein synthesis observed during glucocorticoid treatment. Dexamethasone treatment decreased the effect of insulin on protein synthesis (-35·2%) in epitrochlearis muscle incubated in vitro. This resistance is associated with a total blockage of the stimulation of p70 S6K by insulin without any significant decrease in the amount of the kinase. However, the effect of rapamycin (inhibitor of several intracellular pathways including p70 S6K pathways) on muscle protein synthesis was not modified by dexamethasone in rat muscles. This suggested that 'rapamycin-sensitive pathways' associated with the insulin stimulation of protein synthesis were not altered by glucocorticoids and thus are not responsible for the insulin resistance observed. As incubation of muscles with a MAP kinase inhibitor (PD98059) did not modify the stimulation of protein synthesis by insulin and as glucocorticoids did not alter the effect of insulin on p90 RSK activity, our results provide evidence that glucocorticoidinduced alterations in muscle protein synthesis regulation by insulin do not involve factors or kinases that are dependent on MAP kinase and/or p90 RSK .

Insulin Activates RSK (p90 Ribosomal S6 Kinase) to Trigger a New Negative Feedback Loop That Regulates Insulin Signaling for Glucose Metabolism

“…We also confirmed that S6K, a protein with an amino acid sequence similar to RSK, was not co-immunoprecipitated since a S6K1 inhibitor (PF-4708671) did not interfere with the phosphorylation of GST-S6 protein. These results show that RSK1 is activated in response to insulin stimulation in L6 myocytes, which is in agreement with a previous study showing that RSK could be activated by insulin in the epithroclearis muscle of rats (28).…”

Short-term prednisone use antagonizes insulin's anabolic effect on muscle protein and glucose metabolism in young healthy people

“…The effect of glucocorticoids to interfere with the anabolic response appears to be through the intracellular signaling pathways that are regulated by insulin and amino acids. It was reported that high-dose dexamethasone administration inhibits the insulin-or amino acid-mediated phosphorylation of p70 S6 kinase in rats (6,27,28) and the amino acid effect in humans (14). There was not sufficient muscle tissue samples available to explore these signaling pathways in the present investigation, so further work is needed to determine whether impaired signaling accounts for the effect of Pred to inhibit insulin-mediated muscle anabolism in humans and whether this effect can be reversed through intervention.…”

Hypoglycemic Properties of the Aqueous Extract from the Stem Bark of Ceiba pentandra in Dexamethasone‐Induced Insulin Resistant Rats

“…Many experimental models have been developed to mimic this latter condition among which the glucocorticoid (dexamethasone) model. This experimental metabolic model is already well characterized as being associated with a decrease in body weight [ 10 ]; an increase of glycemia and insulinemia [ 11 , 12 ] which mark the presence of an insulin resistance; a loss in muscle mass associated with liver hypertrophy [ 10 ]; an alteration of protein [ 13 ]; and lipid profiles [ 14 ]. Besides metabolic changes, some cardiovascular alterations have also been described in this model such as arterial hypertension associated with an increased oxidative stress [ 15 , 16 ] and cardiac hypertrophy [ 17 ].…”