Effects of ornithine alpha-ketoglutarate on protein metabolism in Yoshida sarcoma-bearing rats.
OBJECTIVE
Ornithine alpha-ketoglutarate (OKG) is recognized to improve nutritional status in various catabolic states, such as burn injury, trauma, and sepsis. However, in wasting diseases, such as induced by cancer, the data are scarce and the precise mechanisms by which OKG acts on protein metabolism are still unclear. The aim of this study was to evaluate the ability of OKG to affect protein metabolism in an aggressive model of cancer and to modulate the ubiquitin-proteasome-dependent pathway, which in skeletal muscle is the critical degradative pathway implicated in many catabolic states, including cancer-associated cachexia.


METHODS
Experiments were carried out in Yoshida sarcoma-bearing and healthy pair-fed rats. Three groups of 16 young male rats were studied during 9 days following tumor implantation: two groups of tumor-bearing rats fed a balanced regimen enriched with either OKG (5 g/kg body weight/day, OKG-K) or an isonitrogenous mixture of non-essential amino acids (C-K), and one group of healthy pair-fed rats (PF).


RESULTS
As expected, Yoshida sarcoma induced muscle atrophy, decreased nitrogen balance, enhanced 3-methylhistidine (3-MH) excretion and increased mRNA levels for ubiquitin and 14-kDa ubiquitin-conjugating enzyme E2. OKG supplementation did not improve muscle mass or protein balance and did not reduce enhanced 3-MH excretion in Yoshida sarcoma-bearing rats. Furthermore, OKG did not suppress in the cancer rats the enhanced expression of ubiquitin and 14-kDa E2, despite OKG decreased by 23% the ubiquitination rate in cancer rats (OKG-K vs. C-K, P<0.05).


CONCLUSIONS
These data suggest that OKG action is not universal; i.e. depending upon the model under study. In the circumstances, OKG did not counteract the increase in ubiquitin-proteasome-dependent proteolysis observed in Yoshida sarcoma-bearing rats.
Segaud
Frédéric
F
Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie, Université Paris Descartes, 4 Avenue de l'Observatoire, 75270 Paris, Cedex 06, France.
Combaret
Lydie
L
Neveux
Nathalie
N
Attaix
Didier
D
Cynober
Luc
L
Moinard
Christophe
C
D000818:Animals; D008297:Male; D008762:Methylhistidines / Q000652:urine*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000517:prevention & control; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012513:Sarcoma, Experimental / Q000378:metabolism*
D008762:Methylhistidines; D011506:Proteins; C002118:ornithine alpha-ketoglutarate; D009952:Ornithine; C028118:3-methylhistidine