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Role of Akt/GSK-3β/β-Catenin Transduction Pathway in the Muscle Anti-Atrophy Action of Insulin-Like Growth Factor-I in Glucocorticoid-Treated Rats

Université Catholique de Louvain, School of Medicine, Diabetes & Nutrition Unit (O.S., S.K., P.L., J.V., J.M.K., J.P.T.), and Cardiology Unit (L.B.), B-1200 Bruxelles, Belgium

Address all correspondence and requests for reprints to: Olivier Schakman, Unité de Diabétologie et Nutrition, Université Catholique de Louvain, 54 avenue Hippocrate, B-1200 Brussels, Belgium. E-mail: olivier.schakman{at}uclouvain.be.

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 β-catenin protein levels (–40%; P <0.001). Prevention of atrophy by IGF-I was associated with restoration of Akt phosphorylation and β-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-3β (+17%; P <0.05) and in β-catenin content (+35%; P <0.05). Furthermore, overexpression of a dominant-negative GSK-3β or a stable form of β-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-3β, and β-catenin probably contribute together to the IGF-I anti-atrophic effect in GC-induced muscle atrophy.