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

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-3 beta (-17%; P < 0.05) and in beta-catenin content (-35%; P < 0.05). Furthermore, overexpression of a dominant-negative GSK-3 beta 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-3 beta, and beta-catenin probably contribute together to the IGF-I anti-atrophic effect in GC-induced muscle atrophy.