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

Am J Physiol Endocrinol Metab. 2012 Sep 15;303(6):E729-39. doi: 10.1152/ajpendo.00060.2012. Epub 2012 Jun 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Glucocorticoids / adverse effects
  • Glucocorticoids / antagonists & inhibitors
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Insulin-Like Growth Factor I / analysis
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / immunology
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / blood
  • Muscular Atrophy / immunology
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / prevention & control
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis / drug effects
  • RNA, Messenger / metabolism
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation* / drug effects


  • Glucocorticoids
  • I-kappa B Proteins
  • Muscle Proteins
  • NF-kappa B
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • insulin-like growth factor-1, mouse
  • insulin-like growth factor-1, rat
  • Insulin-Like Growth Factor I
  • Proteasome Endopeptidase Complex