Llovera M, Garcia-Martinez C, Agell N, Lopez-Soriano F J, Argiles J M
Departament de Bioquímica i Fisiologia, Facultat de Biologia, Universitat de Barcelona, Spain.
Int J Cancer. 1995 Mar 29;61(1):138-41. doi: 10.1002/ijc.2910610123.
Rats bearing the Yoshida AH-130 ascites hepatoma for 7 days showed an important decrease in muscle mass--over 30% in gastrocnemius and extensor digitorum longus (EDL)--in relation to non-tumour-bearing controls, which is associated with an increased proteolytic rate in in vitro incubation. In order to identify the precise biochemical process which was involved, we measured different proteolytic systems in incubated EDL muscles. The capacity for intralysosomal proteolysis, as measured by sensitivity to methylamine, was not increased in tumour-bearing rats, suggesting that the mechanism involved in the increased proteolytic rate was extralysosomal. Incubations using the Ca2+ ionophore A23187 revealed no change in the activity of calcium-dependent proteases as a consequence of tumour growth. Finally, muscle incubation in an ATP-depleted medium allowed us to conclude that energy-dependent proteases were involved in the activation of muscle proteolysis in tumour-bearing rats. In particular, the ubiquitin-dependent proteolytic system is involved, since there is an important increase in ubiquitin conjugates in the skeletal muscle of tumour-bearing rats. It may thus be suggested that extralysosomal ATP- and ubiquitin-dependent proteases underlie the biochemical mechanism of muscle wastage associated with cancer cachexia.
携带吉田AH - 130腹水肝癌7天的大鼠，与未患肿瘤的对照组相比，肌肉质量显著下降——腓肠肌和趾长伸肌（EDL）下降超过30%，这与体外孵育时蛋白水解速率增加有关。为了确定所涉及的精确生化过程，我们测量了孵育的EDL肌肉中的不同蛋白水解系统。通过对甲胺的敏感性来衡量的溶酶体内蛋白水解能力在患肿瘤大鼠中并未增加，这表明蛋白水解速率增加所涉及的机制是溶酶体外的。使用钙离子载体A23187进行孵育显示，肿瘤生长并未导致钙依赖性蛋白酶的活性发生变化。最后，在ATP耗尽的培养基中孵育肌肉使我们得出结论，能量依赖性蛋白酶参与了患肿瘤大鼠肌肉蛋白水解的激活过程。特别是，泛素依赖性蛋白水解系统参与其中，因为在患肿瘤大鼠的骨骼肌中泛素缀合物有显著增加。因此可以推测，溶酶体外的ATP和泛素依赖性蛋白酶是癌症恶病质相关肌肉消耗生化机制的基础。
