αMSH Blunts Endotoxin-Induced MuRF1 and Atrogin-1 Upregulation in Skeletal Muscle by Modulating NF-κB and Akt/FoxO1 Pathway

Abstract

Alpha melanocyte stimulating hormone (αMSH) has been shown to have anti-inflammatory and anticachectic actions. We hypothesized that αMSH administration could attenuate the effect of lipopolysaccharide (LPS) on the skeletal muscle through modifications in IGF-Akt-FoxO1 pathway, or/and in serum corticosterone. Adult male Wistar rats were injected with LPS and/or αMSH. αMSH administration reduced LPS-induced increase in liver TNFα and serum nitrites as well as NF-κB activation in skeletal muscle. In contrast, αMSH was not able to prevent the stimulatory effect of LPS on serum concentration of ACTH and corticosterone. LPS decreased serum levels of IGF-I and IGFBP3 and their expression in the liver (P < 0.01). However IGFBP3 expression in the gastrocnemius was increased by LPS. Treatment with αMSH prevented the effects of LPS on IGFBP3 but not on IGF-I. In the gastrocnemius αMSH blocked LPS-induced decrease in pAkt as well as the increase in pNF-κB(p65), FoxO1, atrogin-1, and MuRF1 levels. These results suggest that αMSH blunts skeletal muscle response to endotoxin by downregulating atrogenes and FoxO1 at least in part by controlling NF-κB activation and Akt signalling, but not through modifications in the secretion of corticosterone or IGF-I.

Formoterol decreases muscle wasting as well as inflammation in the rat model of rheumatoid arthritis

“…These data differ from those observed in other acute wasting conditions such as lipopolysaccharide (LPS) or glucocorticoid administration, which decrease Akt phosphorylation, whereas the transcription factors Forkhead box-containing protein O subclass (FoxO)-1 and -3a activities are increased (13,44). In cachexia induced by chronic illnesses, the activity of the Akt/FoxO signaling pathway is not well known.…”

“…Furthermore, IGFBP-3 upregulation is mediated by proapoptotic and growth inhibitory factors such as TNF␣ (27). Therefore, it is not surprising that muscle wasting induced by inflammation is associated with increased IGFBP-3 levels, as we have observed not only in arthritis but also after endotoxin injection (44). Taking into account that Akt is a negative regulator of IGFBP-3 (24), the inhibitory action of formoterol treatment on IGFBP-3 in the gastrocnemius can be mediated by the increase in p-Akt and/or the decrease in TNF␣.…”

The melanocortin receptor type 3 agonistd-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats

“…17,18 In this sense, we have recently reported that αMSH prevents endotoxin-induced NF-kB(p65) phosphorylation in the gastrocnemius. 33 These data and the fact that MC3-R is expressed in skeletal muscle 37 suggest that the inhibitory effect of αMSH on NF-kB activation is mediated through MC3-R activation. Furthermore, it has been postulated that MC3-R is the predominant anti-inflammatory receptor for melanocortins.…”

“…In contrast, αMSH treatment is able to decrease anorexia induced by experimental arthritis or lipopolysaccharide (LPS) injection. 23,33 Differences in the effects of the two melanocortins, αMSH and D-Trp(8)-γMSH, on food intake can be due to their different receptor affinities; D-Trp(8)-γMSH is a specific MC3-R agonist, whereas αMSH is a pan-agonist of the MCRs.…”

“…Similarly, αMSH administration prevents the activation of muscle TNF-α/NF-kB pathway and increased expression of atrogenes in rats injected with LPS. 33 Arthritis increased the expression of several genes related to autophagy LC3b, Bnip-3, and Gabarap1. Furthermore, the increased expression of these genes was associated with an increase in both forms of the protein LC3b I and II.…”