Inhibition of muscle insulin-like growth factor I expression by tumor necrosis factor-α

Abstract

The role of TNF-alpha in muscle catabolism is well established, but little is known about the mechanisms of its catabolic action. One possibility could be that TNF-alpha impairs the production of local growth factors like IGF-I. The aim of this study was to investigate whether TNF-alpha can directly inhibit IGF-I gene and protein expression in muscle. First, we investigated whether the acute inflammation induced by endotoxin injection changes IGF-I and TNF-alpha mRNA in rat tibialis anterior muscle. Endotoxin rapidly increased TNF-alpha mRNA (7-fold at 1 h, P < 0.001) and later decreased IGF-I mRNA (-73% at 12 h, P < 0.001). Furthermore, in a model of C2C12 myotubes, TNF-alpha strongly inhibited IGF-I mRNA and protein (-73 and -47% after 72 h, P < 0.001 and P < 0.01, respectively). Other proinflammatory cytokines failed to inhibit IGF-I mRNA. The effect of TNF-alpha on IGF-I mRNA was not mediated by nitric oxide, and the activation of NF-kappaB was insufficient to inhibit IGF-I expression. Taken together, our data suggest that TNF-alpha induced in muscle after LPS injection can locally inhibit IGF-I expression. The inhibition of muscle IGF-I production could contribute to the catabolic effect of TNF-alpha.

Tumour necrosis factor blockade did not prevent the increase of muscular muscle RING finger-1 and muscle atrophy F-box in arthritic rats

“…However, it has been reported (Foulstone et al 2001) that the effects of IGF-I on muscle may depend on the cytokine environment in such a way that in the presence of TNF-a, IGF-I induces apoptosis. The increase in IGF-I gene expression in skeletal muscle of arthritic rats does not correlate with the decrease observed in the muscle of lipopolysaccharide (LPS)-treated rats (Lang et al 2000, Fernández-Celemín et al 2002 and fasting rats (Dehoux et al 2004). The increase in MuRF-1 and MAFbx gene expression found in the skeletal muscle of arthritic rats (Granado et al 2005) has also been found in the muscle of LPS-injected rats (Dehoux et al 2003).…”

“…It has been postulated that TNF-a exerts its catabolic effects in skeletal muscle in a paracrine/autocrine manner (Fernández-Celemín et al 2002). Therefore, the gene expression of E3 ubiquitin ligases MuRF-1 and MAFbx in the muscle of arthritic rats was not changed after PEG-sTNFRI administration probably as a consequence of the lack of effect of this protein complex on muscular TNF-a.…”

“…One possibility is that TNF-a acts directly on skeletal muscle to induce muscle catabolism. Alternatively, TNF-a can act indirectly, stimulating skeletal muscle catabolism by modifying hormones that regulate protein turnover, such as IGF-I (Fernández-Celemín et al 2002) or by inducing anorexia (Tracey et al 1990).…”

Treatment with TNF-α and IFN-γ alters the activation of SER/THR protein kinases and the metabolic response to IGF-I in mouse c2c12 myogenic cells

“…A difference between the short-and long-term effect could be at least partly explained by the changes in receptor function and/or ligand binding, with transient increasing expression of TNF-R1 leading to enhanced protein synthesis, followed by induction of feedback loops, such as the secretion of soluble TNF-R, which sequesters the cytokine [26]. Alternatively, a decrease in autocrine IGF-I production [13,42] could blunt the increase in protein synthesis. The TNF-α concentration effective in causing a decrease in IGF-I-stimulated glucose uptake and protein synthesis can be considered as physiological, i.e.…”

“…The receptors specific for TNF-α, IL-1, IL-6 and IFN-γ are expressed in the skeletal muscle and myogenic cells at a low level, but their contents have been shown to increase noticeably after the induction of inflammation and treatment with a mixture of cytokines in vitro [12], suggesting the existence of local mechanisms enhancing the skeletal muscle response to cytokines. The mechanisms of the catabolic effect of cytokines in the skeletal muscle may involve: a modulation of the activity of the hormones controlling protein metabolism [6]; the inhibition of the production of anabolic factors [13]; and the regulation of the expression of other cytokines [14]. In recent years, there has been a hypothesis regarding hormones and cytokines, which may mutually modulate biological effects via common intracellular signal transduction pathways.…”