Llovera M, García-Martínez C, Agell N, Marzábal M, López-Soriano F J, Argilés J M
Departament de Bioquímica i Fisologia, Facultat de Biologia, Universitat de Barcelona, Spain.
FEBS Lett. 1994 Feb 7;338(3):311-8. doi: 10.1016/0014-5793(94)80290-4.
Rats bearing the fast-growing AH-130 Yoshida ascites hepatoma showed a marked cachectic response which has been previously reported [Tessitore et al. (1987) Biochem. J. 241, 153-159]. Thus tumour-bearing animals showed significant decreases in body and muscle weight (soleus and gastrocnemius) as compared to both pair-fed and ad libitum-fed animals. These decreases were related to an enhanced proteolytic rate in the muscles of the tumour-bearing animals as measured by the tyrosine released in in vitro assays. In an attempt to elucidate which proteolytic system is directly responsible for the decrease in muscle mass, we have studied both lysosomal and non-lysosomal (ATP-dependent) proteolytic systems in this animal model. While the enzymatic activities of the main cathepsin (B and B + L) systems were actually decreased in gastrocnemius muscles of tumour-bearing rats, thus indicating that lysosomal proteolysis was not involved, the ubiquitin pools (both free and conjugated) were markedly altered as a result of tumour burden. These were associated with an increased ubiquitin gene expression in muscle of tumour-bearing rats, over 500% in relation to non-tumour bearers, thus suggesting that the ATP-dependent proteolytic system may be responsible for the muscle proteolysis and wastage observed in this animal tumour model. The fact that we have previously shown that TNF enhances the ubiquitinization of muscle proteins [García-Martínez et al. (1993) FEBS Lett. 323, 211-214], together with the high circulating levels of TNF detected in rats bearing the Yoshida hepatoma allows us to suggest that the cytokine may be responsible, most probably indirectly, for the activation of the referred proteolytic system in tumour-bearing rats.
携带快速生长的AH - 130吉田腹水肝癌的大鼠表现出明显的恶病质反应，这一点先前已有报道[泰西托雷等人（1987年），《生物化学杂志》241卷，第153 - 159页]。因此，与成对喂食和自由进食的动物相比，荷瘤动物的体重和肌肉重量（比目鱼肌和腓肠肌）显著下降。这些下降与荷瘤动物肌肉中蛋白水解速率的提高有关，这是通过体外实验中释放的酪氨酸来测量的。为了阐明哪种蛋白水解系统直接导致肌肉质量下降，我们在这个动物模型中研究了溶酶体和非溶酶体（ATP依赖型）蛋白水解系统。虽然在荷瘤大鼠的腓肠肌中，主要组织蛋白酶（B和B + L）系统的酶活性实际上有所下降，这表明溶酶体蛋白水解不参与其中，但由于肿瘤负荷，泛素池（游离和结合的）发生了显著变化。这些变化与荷瘤大鼠肌肉中泛素基因表达的增加有关，相对于非荷瘤大鼠增加了500%以上，因此表明ATP依赖型蛋白水解系统可能是导致该动物肿瘤模型中观察到的肌肉蛋白水解和消瘦的原因。我们之前已经表明肿瘤坏死因子会增强肌肉蛋白的泛素化[加西亚 - 马丁内斯等人（1993年），《欧洲生物化学学会联合会快报》323卷，第211 - 214页]，再加上在携带吉田肝癌的大鼠中检测到的高循环水平的肿瘤坏死因子，这使我们认为这种细胞因子很可能间接导致了荷瘤大鼠中上述蛋白水解系统的激活。
