Role of IGF-I and TNF-α/NF-κB pathway in the induction of muscle atrogenes by acute inflammation.

Several catabolic states (sepsis, cancer ...) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor Nuclear Factor kappa B (NF-κB), induced by Tumor Necrosis Factor (TNF)-α and the transcription factor Forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by Insulin like Growth Factor (IGF)-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by Lipopolysaccharide (LPS) injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNF-α together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNF-α production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent either the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU486 blunted completely the activation of these atrogenes by LPS. In conclusion, we showed that increased GC production plays a more crucial role than decreased IGF-I and increased TNF-α/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation

Urotensin II induction of adult cardiomyocytes hypertrophy involves the Akt/GSK-3beta signaling pathway.

Urotensin II (UII) a potent vasoactive peptide is upregulated in the failing heart and promotes cardiomyocytes hypertrophy, in particular through mitogen-activated protein kinases. However, the regulation by UII of GSK-3beta, a recognized pivotal signaling element of cardiac hypertrophy has not yet been documented. We therefore investigated in adult cardiomyocytes, if UII phosphorylates GSK-3beta and Akt, one of its upstream regulators and stabilizes beta-catenin, a GSK-3beta dependent nuclear transcriptional co-activator. Primary cultures of adult rat cardiomyocytes were stimulated for 48h with UII. Cell size and protein/DNA contents were determined. Phosphorylated and total forms of Akt, GSK-3beta and the total amount of beta-catenin were quantified by Western blot. The responses of cardiomyocytes to UII were also evaluated after pretreatment with the chemical phosphatidyl-inositol-3-kinase inhibitor, LY294002, and urantide, a competitive UII receptor antagonist. UII increased cell size and the protein/DNA ratio, consistent with a hypertrophic response. UII also increased phosphorylation of Akt and its downstream target GSK-3beta. beta-catenin protein levels were increased. All of these effects of UII were prevented by LY294002, and urantide. The UII-induced adult cardiomyocytes hypertrophy involves the Akt/GSK-3beta signaling pathways and is accompanied by the stabilization of the beta-catenin. All these effects are abolished by competitive inhibition of the UII receptor, consistent with new therapeutic perspectives for heart failure treatment

Urocortin-induced cardiomyocytes hypertrophy is associated with regulation of the GSK-3β pathway

Urocortin-1 (UCN), a member of the corticotropin-releasing factor, is a cardioprotective peptide, and is also involved in cardiac hypertrophy. The involvement of GSK-3β, a pivotal kinase in cardiac hypertrophy, in response to UCN is not yet documented. Cardiomyocytes from adult rats were stimulated for 48 h with UCN. Cell size, protein, and DNA contents were determined. Phosphorylated and total forms GSK-3β and the total amount of β-catenin were quantified by Western immunoblots. The effects of astressin, a UCN competitive receptor antagonist, were also evaluated. UCN increased cell size and the protein-to-DNA ratio, in accordance with a hypertrophic response. This effect was associated with increased phosphorylation of GSK-3β and marked accumulation of β-catenin, a downstream element to GSK-3β. All these effects were prevented by astressin and LY294002, an inhibitor of the phosphatidyl-inositol-3-kinase. UCN-induced cardiomyocytes hypertrophy is associated with regulation of GSK-3β, a pivotal kinase involved in cardiac hypertrophy, in a PI3K-dependent manner. Furthermore, the pharmacological blockade of UCN receptors was able to prevent UCN-induced hypertrophy, which leads to inhibition of the Akt/GSK-3β pathway