15927518

pubmed:Citation

10

We and others reported previously that IGF-I inhibits dexamethasone-induced proteolysis in cultured L6 myotubes. Recent evidence suggests that this effect of IGF-I at least in part reflects PI3K/Akt-mediated inhibition of Foxo transcription factors. The potential role of other mechanisms, downstream of PI3K/Akt, is not well understood. Here we tested the hypothesis that PI3K/Akt-mediated inactivation of GSK-3beta and activation of mTOR contribute to the anabolic effects of IGF-I in dexamethasone-treated myotubes. Cultured L6 myotubes were treated with 1 microM dexamethasone in the absence or presence of 0.1 microg/ml of IGF-I and inhibitors of GSK-3beta and mTOR. Protein degradation was measured by determining the release of trichloroacetic acid soluble radioactivity from myotubes that had been prelabeled with (3)H-tyrosine for 48 h. IGF-I reduced basal protein breakdown rates and completely abolished the dexamethasone-induced increase in myotube proteolysis. These effects of IGF-I were associated with increased phosphorylation of Akt, GSK-3beta, and the mTOR downstream targets p70(S6K) and 4E-BP1. The PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin reversed the anabolic effect of IGF-I in dexamethasone-treated myotubes. In addition, the GSK-3beta inhibitors LiCl and TDZD-8 reduced protein degradation in a similar fashion as IGF-I. Our results suggest that PI3K/Akt-mediated inactivation of GSK-3beta and activation of mTOR contribute to the anabolic effects of IGF-I in dexamethasone-treated myotubes.

eng

IM

MEDLINE

1357-2725

Print

NLM

2207-16

pubmed-meshheading:15927518-Animals, pubmed-meshheading:15927518-Cells, Cultured, pubmed-meshheading:15927518-Chromones, pubmed-meshheading:15927518-Dexamethasone, pubmed-meshheading:15927518-Dose-Response Relationship, Drug, pubmed-meshheading:15927518-Flavonoids, pubmed-meshheading:15927518-Glycogen Synthase Kinase 3, pubmed-meshheading:15927518-Humans, pubmed-meshheading:15927518-Insulin-Like Growth Factor I, pubmed-meshheading:15927518-Lithium Chloride, pubmed-meshheading:15927518-MAP Kinase Signaling System, pubmed-meshheading:15927518-Models, Biological, pubmed-meshheading:15927518-Morpholines, pubmed-meshheading:15927518-Muscle Fibers, Skeletal, pubmed-meshheading:15927518-Muscle Proteins, pubmed-meshheading:15927518-Phosphatidylinositol 3-Kinases, pubmed-meshheading:15927518-Protein Kinases, pubmed-meshheading:15927518-Rats, pubmed-meshheading:15927518-Sirolimus, pubmed-meshheading:15927518-TOR Serine-Threonine Kinases, pubmed-meshheading:15927518-Thiadiazoles

Insulin-like growth factor-I inhibits dexamethasone-induced proteolysis in cultured L6 myotubes through PI3K/Akt/GSK-3beta and PI3K/Akt/mTOR-dependent mechanisms.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural