IGF-1 is downregulated in experimental cancer cachexia.
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.
Costelli
Paola
P
Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Turin, Italy. paola.costelli@unito.it
Muscaritoli
Maurizio
M
Bossola
Maurizio
M
Penna
Fabio
F
Reffo
Patrizia
P
Bonetto
Andrea
A
Busquets
Silvia
S
Bonelli
Gabriella
G
Lopez-Soriano
Francisco J
FJ
Doglietto
Giovanni Battista
GB
Argilés
Josep M
JM
Baccino
Francesco M
FM
Rossi Fanelli
Filippo
F
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002100:Cachexia / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010431:Pentoxifylline / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1; D010431:Pentoxifylline; D000068759:Formoterol Fumarate