Decrease of muscle Insulin-like Growth Factor (IGF)-I plays a critical role in muscle atrophy caused by glucocorticoids (GC), as IGF-I gene electrotransfer prevents muscle atrophy caused by GC. 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 -catenin protein levels (-40%, P <0.001). Prevention of atrophy by IGF-I was associated with restoration of Akt phosphorylation and -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 [CSA]; P <0.001), and prevented dexa-induced atrophy. This hypertrophy was associated with an increase in phosphorylated GSK-3 (+17%, P <0.05) and in -catenin content (+35%, P <0.05). Furthermore, overexpression of a dominant negative GSK-3 or a stable form of -catenin increased fiber CSA 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-3 and -catenin probably contribute together to the IGF-I anti-atrophic effect in GC-induced muscle atrophy.