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.
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.
Schakman
O
O
Université Catholique de Louvain, School of Medicine, Diabetes & Nutrition Unit, B-1200 Bruxelles, Belgium. olivier.schakman@uclouvain.be
Kalista
S
S
Bertrand
L
L
Lause
P
P
Verniers
J
J
Ketelslegers
J M
JM
Thissen
J P
JP
D000818:Animals; D019610:Cytoprotection / Q000235:genetics*; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D005938:Glucocorticoids / Q000009:adverse effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
D005938:Glucocorticoids; D051176:beta Catenin; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D038362:Glycogen Synthase Kinase 3