Muscle atrophy in experimental cancer cachexia: is the IGF-1 signaling pathway involved?
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 GSK3beta, p70(S6K) and FoxO1 were hyperphosphorylated, while the levels of phosphorylated eIF2alpha 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.
Penna
Fabio
F
Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy.
Bonetto
Andrea
A
Muscaritoli
Maurizio
M
Costamagna
Domiziana
D
Minero
Valerio Giacomo
VG
Bonelli
Gabriella
G
Rossi Fanelli
Filippo
F
Baccino
Francesco Maria
FM
Costelli
Paola
P
D000818:Animals; D002100:Cachexia / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000473:pathology; D018274:Electroporation / Q000379:methods; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D008113:Liver Neoplasms / Q000150:complications / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009133:Muscular Atrophy / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D010957:Plasmids; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D051858:Forkhead Transcription Factors; D007334:Insulin-Like Growth Factor I