IGF-1 is downregulated in experimental cancer cachexia

Am J Physiol Regul Integr Comp Physiol. 2006 Sep;291(3):R674-83. doi: 10.1152/ajpregu.00104.2006. Epub 2006 Apr 13.


Cancer cachexia is characterized by skeletal muscle wasting that is mainly supported by hypercatabolism. Muscle atrophy has been suggested to depend on impaired IGF-1 signal transduction pathway. The present study has been aimed at investigating the IGF-1 system in rats bearing the AH-130 hepatoma, a well-characterized model of cachexia. IGF-1 mRNA expression in the gastrocnemius of tumor hosts progressively decreases to approximately 50% of controls. By contrast, both IGF-1 receptor and insulin receptor mRNA levels increase in day 7 AH-130 hosts. IGF-1 and insulin circulating levels, as well as IGF-1 expression in the liver, are reduced. Muscle wasting in the AH-130 bearers is associated with hyperactivation of the ubiquitin-proteasome system. Consistently, the mRNA levels of ubiquitin and of the ubiquitin ligases atrogin-1 and MuRF1 are significantly increased in the gastrocnemius of day 7 AH-130 hosts. Exogenous IGF-1 administered to tumor bearers does not prevent cachexia. IGF-1 mRNA levels also have been evaluated in the gastrocnemius of AH-130 hosts treated with pentoxifylline, an inhibitor of TNF-alpha synthesis, alone or combined with formoterol, a beta(2)-adrenergic agonist. Both treatments partially correct muscle atrophy without modifying IGF-1 and atrogin-1 mRNA levels, whereas MuRF1 hyperexpression is reduced by the combination of pentoxifylline with formoterol. These results demonstrate for the first time that the IGF-1 system is downregulated in cancer cachexia, although the underlying mechanism remains unknown. Moreover, no simple relation linking IGF-1 and/or atrogin-1 mRNA levels and muscle atrophy could be observed in these experimental conditions. Further studies are thus needed to clarify both issues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Cachexia / metabolism*
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology
  • Ethanolamines / pharmacology
  • Formoterol Fumarate
  • Gene Expression Regulation
  • Insulin-Like Growth Factor I / metabolism*
  • Male
  • Muscle Proteins / metabolism
  • Muscle, Skeletal
  • Neoplasms, Experimental / metabolism*
  • Pentoxifylline / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, IGF Type 1 / metabolism
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Tripartite Motif Proteins
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism


  • Adrenergic beta-Agonists
  • Enzyme Inhibitors
  • Ethanolamines
  • Muscle Proteins
  • Tripartite Motif Proteins
  • Ubiquitin
  • Insulin-Like Growth Factor I
  • Fbxo32 protein, rat
  • SKP Cullin F-Box Protein Ligases
  • Trim63 protein, rat
  • Ubiquitin-Protein Ligases
  • Receptor, IGF Type 1
  • Pentoxifylline
  • Formoterol Fumarate