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Mechanisms involved in cAMP mediated inhibition of the Ubiquitin‐Proteasome system
Author(s) -
Lira Eduardo Carvalho,
Gonçalves Dawit Albieiro,
Za Neusa M.,
Baviera Amanda M.,
Bedard Nathalie,
Wing Simon S.,
Kettelhut Ísis do Carmo,
Navegantes Luiz Carlos
Publication year - 2008
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.22.1_supplement.962.5
Subject(s) - ibmx , clenbuterol , ubiquitin , medicine , endocrinology , protein kinase b , proteasome , chemistry , skeletal muscle , phosphorylation , foxo3 , myocyte , stimulation , biology , biochemistry , forskolin , gene
Aim: This study was undertaken to investigate the role of beta‐2 adrenoceptors and cAMP in regulating the Ubiquitin‐proteasome system (UPS) in skeletal muscle from normal rats. Methods and results: The activity of UPS and the Akt/FoxO signaling pathway were measured in skeletal muscle from rats treated with clenbuterol (3 mg/kg wt; sc), a selective beta‐2 adrenergic agonist, for 3 days. In extensor digital longus (EDL) muscle, clenbuterol increased by 30% muscle weight, reduced by 45% the UPS activity and increased by 30% the phosphorylation of Akt and FoxO3. The addition of isobutylmethylxanthine (IBMX; 10 −3 M), a cAMP phosphodiesterase inhibitor, to the incubation medium increased cAMP levels (4‐fold) and decreased by 50% the UPS activity in isolated soleus and EDL muscles from normal rats. IBMX in vitro also reduced the levels of ubiquitin‐protein conjugated and the mRNA levels of the atrogin‐1/MAF bx (50%) and the E 2 ‐14KDa ubiquitin conjugating enzyme (30%) transcripts in muscles from normal rats. Ubiquitin and MuRF1 mRNA were not altered by IBMX in vitro. Conclusions: These data suggest that stimulation of beta‐2 adrenoceptors, through the activation of cAMP and Akt signaling pathways, inhibit ubiquitin‐proteasome proteolysis by increasing FoxO3 phosphorylation and suppressing atrogin‐1 mRNA expression in skeletal muscle from normal rats. Financial support: CNPq, CAPES, FAPESP