Fabio Penna and Andrea Bonetto contributed equally to this work
Muscle atrophy in experimental cancer cachexia: Is the IGF-1 signaling pathway involved?
Article first published online: 28 DEC 2009
Copyright © 2009 UICC
International Journal of Cancer
Volume 127, Issue 7, pages 1706–1717, 1 October 2010
How to Cite
Penna, F., Bonetto, A., Muscaritoli, M., Costamagna, D., Minero, V. G., Bonelli, G., Fanelli, F. R., Baccino, F. M. and Costelli, P. (2010), Muscle atrophy in experimental cancer cachexia: Is the IGF-1 signaling pathway involved?. Int. J. Cancer, 127: 1706–1717. doi: 10.1002/ijc.25146
- Issue published online: 4 AUG 2010
- Article first published online: 28 DEC 2009
- Manuscript Accepted: 17 DEC 2009
- Manuscript Received: 21 SEP 2009
- Ministero per l'Università e la Ricerca, Rome (PRIN projects)
- University of Turin (ex-60% funds)
- Regione Piemonte and Associazione Italiana per la Ricerca sul Cancro (AIRC)Fabio Penna and Andrea Bonetto contributed equally to this work.
- cancer cachexia;
- muscle wasting;
Skeletal muscle wasting, one of the main features of cancer cachexia, is associated with marked protein hypercatabolism, and has suggested to depend also on impaired IGF-1 signal transduction pathway. To investigate this point, the state of activation of the IGF-1 system has been evaluated both in rats bearing the AH-130 hepatoma and in mice transplanted with the C26 colon adenocarcinoma. In the skeletal muscle of tumor hosts, the levels of phosphorylated (active) Akt, one of the most relevant kinases involved in the IGF-1 signaling pathway, were comparable to controls, or even increased. Accordingly, downstream targets such as GSK3β, p70S6K and FoxO1 were hyperphosphorylated, while the levels of phosphorylated eIF2α were markedly reduced with respect to controls. In the attempt to force the metabolic balance toward anabolism, IGF-1 was hyperexpressed by gene transfer in the tibialis muscle of the C26 hosts. In healthy animals, IGF-1 overexpression markedly increased both fiber and muscle size. As a positive control, IGF-1 was also overexpressed in the muscle of aged mice. In IGF-1 hyperexpressing muscles the fiber cross-sectional area definitely increased in both young and aged animals, while, by contrast, loss of muscle mass or reduction of fiber size in mice bearing the C26 tumor were not modified. These results demonstrate that muscle wasting in tumor-bearing animals is not associated with downregulation of molecules involved in the anabolic response, and appears inconsistent, at least, with reduced activity of the IGF-1 signaling pathway.