Anticytokine treatment prevents the increase in the activity of ATP-ubiquitin- and Ca(2+)-dependent proteolytic systems in the muscle of tumour-bearing rats.
The ascites hepatoma Yoshida AH-130 induces loss of body weight and tissue waste. Tumour necrosis factor alpha (TNF-alpha) plays a pivotal role in the pathogenesis of muscle wasting in this model system, but other cytokines, such as interleukin-6, may be involved. In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation, tumour bearing rats were treated with pentoxyfilline (PTX, an inhibitor of TNF-alpha synthesis), or with suramin (SUR, an antiprotozoal drug blocking the peripheral action of several cytokines including IL-6 and TNF-alpha), or both the drugs, and the effects on muscle proteolytic systems were assessed. Muscle protein loss in the AH-130-bearing rats was associated with increased activity of both the ATP-ubiquitin- and the calpain- dependent proteolytic pathways (246% and 230% of controls, respectively). Both PTX and SUR, either alone or in combination, prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems. In particular, treatment with SUR, either alone or with PTX, induced a decrease in enzymatic activities to values similar to those of controls. The results obtained in the present paper demonstrate that: (i) muscle depletion in this model is indeed associated with increased proteasome- and calpain-dependent proteolysis, as previously suggested by increased mRNA expression of molecules pertaining to both pathways; (ii) anticytokine treatments effectively reduce muscle protein loss by down-regulating the activity of at least two major proteolitic systems; (iii) SUR is more effective than PTX in reducing the activity of proteolytic systems, possibly because of its multiple anticytokine action.
Costelli
P
P
Dipartimento di Medicina ed Oncologia Spermentale, Universitá di Toroino, Torino, Italy. paola.costelli@unito.it
Bossola
M
M
Muscaritoli
M
M
Grieco
G
G
Bonelli
G
G
Bellantone
R
R
Doglietto
G B
GB
Baccino
F M
FM
Rossi Fanelli
F
F
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors*; D015536:Down-Regulation; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
D016207:Cytokines; D015850:Interleukin-6; D009097:Multienzyme Complexes; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002118:Calcium