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ß 2 ‐Adrenergic Agonist Suppresses Foxo Transcriptional Activity by Regulating Foxo1 Phosphorylation but not Acetylation in Skeletal Muscle
Author(s) -
Goncalves Dawit,
Manfredi Leandro,
Graça Flávia,
Silveira Wilian,
Lustrino Danilo,
Kettelhut Isis,
Navegantes Luiz Carlos
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb702
Subject(s) - foxo1 , creb , phosphorylation , protein kinase b , endocrinology , medicine , chemistry , creb binding protein , agonist , skeletal muscle , biology , receptor , biochemistry , transcription factor , gene
This study was undertaken to identify: 1) whether ß 2 ‐adrenergic agonist (BA) suppresses Foxo transcriptional activity and the expression of atrophy‐related genes (atrogenes) in skeletal muscles and 2) which post‐translational modification [ i.e., phosphorylation (p) and acetylation (ac)] is related to the inhibition of Foxo1. For that, we examined Formoterol (FOR), a newer generation of BA, effects on the levels of p‐Foxo1, ac‐Foxo1, p‐Akt and p‐CREB, a canonical target of BA signaling, by immunoblotting, the activity of Foxo by reporter luciferase assay and the mRNA levels of atrogenes (Atrogin‐1, MuRF1 and Gabarapl1) by qPCR in muscles from 2‐d fasted rodents. Fasting reduced p‐Akt (~80%) and p‐Foxo1 (30%) and increased Foxo activity (~15‐fold) and atrogenes expression (~7‐fold). Thirty min after an injection, FOR in vivo (300 μg.kg ‐1 ) caused an elevation in p‐Akt (~10‐fold), p‐Foxo1 (2‐fold) and p‐CREB (2‐fold). At 4h, FOR reduced Foxo activity (~40%) and atrogenes mRNAs (~40%). In isolated muscles from fasted rats, FOR in vitro (10 ‐4 M) also increased p‐Foxo1, p‐Akt and p‐CREB. Ac‐Foxo1 levels did not alter in any condition. These data suggest FOR counteracts the up‐regulation of atrogenes induced by food deprivation in muscle by activating Akt and inhibiting Foxo. In addition, these effects seem to be related to the induction of Foxo1 phosphorylation, but not acetylation. Supported by FAPESP ( 12/18861‐0 and 12/24524‐6 ).