Protein Breakdown in Muscle from Burned Rats Is Blocked by Insulin-Like Growth Factor I and Glycogen Synthase Kinase-3β Inhibitors
| Autor: | Per-Olof Hasselgren, Amy Evenson, Cheng-Hui Fang, Jy-Kung King, Glenn D. Warden, Bing-Guo Li, J. Howard James |
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| Rok vydání: | 2005 |
| Předmět: |
Male
MAPK/ERK pathway medicine.medical_specialty Muscle Proteins Nerve Tissue Proteins Protein Serine-Threonine Kinases Rats Sprague-Dawley Wortmannin Glycogen Synthase Kinase 3 Phosphatidylinositol 3-Kinases chemistry.chemical_compound Endocrinology GSK-3 Proto-Oncogene Proteins Internal medicine Thiadiazoles medicine Animals Enzyme Inhibitors Insulin-Like Growth Factor I Phosphorylation Muscle Skeletal Glycogen synthase PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Glycogen Synthase Kinase 3 beta biology Akt/PKB signaling pathway Skeletal muscle Forkhead Transcription Factors Toes Hindlimb Rats DNA-Binding Proteins Enzyme Activation medicine.anatomical_structure chemistry biology.protein Burns Lithium Chloride Proto-Oncogene Proteins c-akt Peptide Hydrolases |
| Zdroj: | Endocrinology. 146:3141-3149 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2004-0869 |
| Popis: | We reported previously that IGF-I inhibits burn-induced muscle proteolysis. Recent studies suggest that activation of the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway with downstream phosphorylation of Forkhead box O transcription factors is an important mechanism of IGF-I-induced anabolic effects in skeletal muscle. The potential roles of other mechanisms in the anabolic effects of IGF-I are less well understood. In this study we tested the roles of mammalian target of rapamycin and glycogen synthase kinase-3β (GSK-3β) phosphorylation as well as MAPK- and calcineurin-dependent signaling pathways in the anticatabolic effects of IGF-I by incubating extensor digitorum longus muscles from burned rats in the presence of IGF-I and specific signaling pathway inhibitors. Surprisingly, the PI3K inhibitors LY294002 and wortmannin reduced basal protein breakdown. No additional inhibition by IGF-I was noticed in the presence of LY294002 or wortmannin. Inhibition of proteolysis by IGF-I was associated with phosphorylation (inactivation) of GSK-3β. In addition, the GSK-3β inhibitors, lithium chloride and thiadiazolidinone-8, reduced protein breakdown in a similar fashion as IGF-I. Lithium chloride, but not thiadiazolidinone-8, increased the levels of phosphorylated Foxo 1 in incubated muscles from burned rats. Inhibitors of mammalian target of rapamycin, MAPK, and calcineurin did not prevent the IGF-I-induced inhibition of muscle proteolysis. Our results suggest that IGF-I inhibits protein breakdown at least in part through a PI3K/Akt/GSK3β-dependent mechanism. Additional experiments showed that similar mechanisms were responsible for the effect of IGF-I in muscle from nonburned rats. Taken together with recent reports in the literature, the present results suggest that IGF-I inhibits protein breakdown in skeletal muscle by multiple mechanisms, including PI3K/Akt-mediated inactivation of GSK-3β and Foxo transcription factors. |
| Databáze: | OpenAIRE |
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