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

Abstract

Several catabolic states (sepsis, cancer, etc.) 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 NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by 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 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 TNFα 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 TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction

“…42 We found that total FOXO-1 expression was increased in CI peritonitis groups ( Figure 5B). This finding is in agreement with previous reports that suggested that both cecal ligation and puncture (CLP)-and lipopolysaccharide (LPS)-induced sepsis models are associated with increased skeletal muscle FOXO-1 mRNA 43,44 and protein levels. 45 Conversely, we noted that peritonitis was associated with diminished ratio of Akt and FOXO-1 phosphorylated (active)/total protein and that this ratio that appeared to be attenuated with the treatment (Figure 5A and B).…”

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…Upregulated gene and/or protein expression of several components of the autophagy-lysosome system and/or accumulation of autophagic vacuoles has been observed in skeletal muscle of experimental models of acute and prolonged critical illness (55,322,434,490,616,690). Muscle disuse may be an important factor since multiple (though not all) studies on denervation-induced atrophy (model of chronic muscle disuse) also found such alterations, with one study additionally showing an increase in autophagic flux (356,525,526,715).…”

Cross-talk between skeletal muscle and immune cells: muscle-derived mediators and metabolic implications

“…Similarly, in vivo, inoculation with low doses of LPS provokes an increase in TNF␣ and IL-6 mRNA in human skeletal muscle (4) and causes CCL2 expression in mouse diaphragm (67). LPS administration to mice in vivo activates muscle tissue proteolysis, induced by a systemic rise in glucocorticoids and independent of muscle TNF␣ expression or NF-B signaling (123). Collectively, these studies show that muscle cells and tissue respond acutely to endotoxin (LPS) with a proinflammatory response that includes release of CCL2 and cytokine expression, which may in turn contribute to immune cell chemoattraction.…”