Role of Akt/GSK-3beta/beta-catenin transduction pathway in the muscle anti-atrophy action of insulin-like growth factor-I in glucocorticoid-treated rats.

Abstract

Decrease of muscle IGF-I plays a critical role in muscle atrophy caused by glucocorticoids (GCs) because IGF-I gene electrotransfer prevents muscle atrophy caused by GCs. The goal of the present study was to identify the intracellular mediators responsible for the IGF-I anti-atrophic action in GC-induced muscle atrophy. We first assessed the IGF-I transduction pathway alterations caused by GC administration and their reversibility by local IGF-I overexpression performed by electrotransfer. Muscle atrophy induced by dexamethasone (dexa) administration occurred with a decrease in Akt (-53%; P<0.01) phosphorylation together with a decrease in beta-catenin protein levels (-40%; P<0.001). Prevention of atrophy by IGF-I was associated with restoration of Akt phosphorylation and beta-catenin levels. We then investigated whether muscle overexpression of these intracellular mediators could mimic the IGF-I anti-atrophic effects. Overexpression of a constitutively active form of Akt induced a marked fiber hypertrophy in dexa-treated animals (+175% of cross-sectional area; P<0.001) and prevented dexa-induced atrophy. This hypertrophy was associated with an increase in phosphorylated GSK-3beta (+17%; P<0.05) and in beta-catenin content (+35%; P<0.05). Furthermore, overexpression of a dominant-negative GSK-3beta or a stable form of beta-catenin increased fiber cross-sectional area by, respectively, 23% (P<0.001) and 29% (P<0.001) in dexa-treated rats, preventing completely the atrophic effect of GC. In conclusion, this work indicates that Akt, GSK-3beta, and beta-catenin probably contribute together to the IGF-I anti-atrophic effect in GC-induced muscle atrophy.

• Authors: O Schakman, S Kalista, L Bertrand, P Lause, J Verniers, J M Ketelslegers, J P Thissen
• Journal: Endocrinology (Endocrinology) Vol. 149 Issue 8 Pg. 3900-8 (Aug 2008) ISSN: 0013-7227 [Print] United States
• PMID: 18467435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucocorticoids
• beta Catenin
• Insulin-Like Growth Factor I
• Dexamethasone
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• ribosomal protein S6 kinase, 70kD, polypeptide 2
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cytoprotection (genetics)
• Dexamethasone (administration & dosage, adverse effects)
• Glucocorticoids (adverse effects)
• Glycogen Synthase Kinase 3 (genetics, physiology)
• Glycogen Synthase Kinase 3 beta
• Insulin-Like Growth Factor I (genetics)
• Male
• Muscular Atrophy (chemically induced, genetics)
• Organ Specificity (genetics)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, physiology)
• Rats
• Rats, Wistar
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors)
• Signal Transduction (physiology)
• Transfection
• beta Catenin (genetics, physiology)