Involvement of cAMP/Epac/PI3K-dependent pathway in the antiproteolytic effect of epinephrine on rat skeletal muscle

Abstract

Very little is known about the signaling pathways by which catecholamines exert anabolic effects on muscle protein metabolism, stimulating protein synthesis and suppressing proteolysis. The present work tested the hypothesis that epinephrine-induced inhibition of muscle proteolysis is mediated through the cAMP/Epac/PI3K-dependent pathway with the involvement of AKT and Foxo. The incubation of extensor digitorum longus (EDL) muscles from rats with epinephrine and/or insulin increased the phosphorylation of AKT and its downstream target Foxo3a, a well-known effect that prevents Foxo translocation to the nucleus and the activation of proteolysis. Similar effects on AKT/Foxo signaling were observed in muscles incubated with DBcAMP (cAMP analog). The stimulatory effect of epinephrine on AKT phosphorylation was completely blocked by wortmannin (selective PI3K inhibitor), suggesting that the epinephrine-induced activation of AKT is mediated through PI3K. As for epinephrine and DBcAMP, the incubation of muscles with 8CPT-2Me-cAMP (selective Epac agonist) reduced rates of proteolysis and increased phosphorylation levels of AKT and Foxo3a. The specific PKA agonist (N6BZ-cAMP) inhibited proteolysis and abolished the epinephrine-induced AKT and Foxo3a phosphorylation. On the other hand, inhibition of PKA by H89 further increased the phosphorylation levels of AKT and Foxo3a induced by epinephrine, DBcAMP or 8CPT-2Me-cAMP. These findings suggest that the antiproteolytic effect of the epinephrine on isolated skeletal muscle may occur through a cAMP/Epac/PI3K-dependent pathway, which leads to the phosphorylation of AKT and Foxo3a. The parallel activation of PKA-dependent pathway also inhibits proteolysis and seems to limit the stimulatory effect of cAMP on AKT/Foxo3a signaling.

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

“…The effect of cAMP on the PI3Kinase pathway has been described to differ between cell types as the two main effectors of cAMP: protein kinase A and EPAC have been reported to have opposing effects on the pathway (Smith et al 2005, Chen et al 2007, Kwak et al 2008, Baviera et al 2010. In the present set of experiments, the effect of cAMP seems to be inhibitory on the FOXO3A/AKT1 phosphorylation.…”

“…This occurs within 6 h after activation of the pathway (Li et al 2010). It is possible that cAMP interacts with the PI3Kinase pathway through exchange protein directly activated by cAMP (EPAC) in the oocyte as seen in skeletal muscle (Baviera et al 2010). Alternatively, cAMP may increase the production of Kit ligand (KITLG), also known as stem cell factor, in the granulosa cells (GC) as gene expression of KITLG has been shown to be stimulated by cAMP in Sertolli cells, and in ovarian cancer cells (Shaw et al 2002, Grimaldi et al 2003.…”

Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

“…26,47 Interestingly, an important role for the PI3K/AKT pathway has been shown to stimulate FOXO3A and FOXG1 phosphorylation via epinephrine or IGF1, respectively. 9,49 The PI3K/AKT pathway is also known to be important as an amplification signaling pathway for initial platelet activation via epinephrine 50 and ADP. 51 Further studies are needed to define whether FOXG1 is also essential in this pathway to obtain full platelet activation.…”

Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

“…Interestingly however, they reported that a PI3K inhibitor wortmannin also inhibited cAMP-analogue enhanced eosinophil survival. Even though the PI3K-Akt pathway is not classically considered as a signalling pathway of β 2 -agonists and cAMP-elevating agents, it is tempting to speculate, that β 2 -agonist mediated eosinophil survival could follow β-receptoradenylyl cyclase -cAMP -PKA -PI3K -Akt pathway as recent reports suggest [25][26][27].…”