Carbó Neus, Costelli Paola, Busquets Sílvia, López-Soriano Joaquín, López-Soriano Francisco J, Baccino Francesco M, Argilés Josep M
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Diagonal 645, 08028-Barcelona, Spain.
Int J Mol Med. 2004 Oct;14(4):719-23.
Overexpression of the proto-oncogene c-ski in mice results in the development of a hypertrophic phenotype, characterized by increases in body and muscle weights. It has been previously shown in our laboratories that down-regulation of muscle protein breakdown associated with reduced expression of genes pertaining to different proteolytic systems likely account for this hypertrophic pattern. The aim of the present study was to evaluate the resistance of c-ski transgenic mice to catabolic stimuli such as those induced by the growth of the Lewis lung carcinoma. The tumor elicited a loss of body weight either in transgenic or in non-transgenic animals, although it was less pronounced in the former. The mass of gastrocnemius, tibialis and extensor digitorum longus (EDL) muscles were significantly reduced in non-transgenic tumor-bearing mice. Despite the anabolic setting displayed by the transgenic animals, the EDL only is completely protected against wasting. Indeed, gastrocnemius, tibialis and soleus show a reduction in weight, the latter two being significantly more depleted when compared to the non-transgenic tumor bearers. Similarly, the perigenital white adipose tissue presented a reduced mass which was more marked in the transgenic group. The quantitation of gene expression for ubiquitin, E2, C8 and calpain in the EDL showed marked differences between the transgenic and the non-transgenic groups of tumor hosts. As expected from previous results, in the latter group most of the transcripts examined increased with respect to controls as a consequence of tumor growth; by contrast, in the transgenic tumor hosts there was a significant reduction of ubiquitin, E2, C8 subunit, and calpain mRNA levels in comparison with the transgenic tumor-free animals. These results show that c-ski hyperexpression prevents tumor-induced muscle wasting in the EDL muscle, likely by impairing the state of activation of different proteolytic systems. However, the lack of effectiveness in the other muscles examined suggests that the achievement of a significant interference with the development of cachexia at the molecular level is not an easy task and probably should be designed taking into consideration more than one target.
原癌基因c-ski在小鼠中的过表达导致肥大表型的发展，其特征是体重和肌肉重量增加。我们实验室先前已经表明，与不同蛋白水解系统相关基因表达降低相关的肌肉蛋白分解下调可能是这种肥大模式的原因。本研究的目的是评估c-ski转基因小鼠对分解代谢刺激的抵抗力，例如由Lewis肺癌生长诱导的刺激。肿瘤在转基因和非转基因动物中均引起体重减轻，尽管在前者中不太明显。非转基因荷瘤小鼠的腓肠肌、胫骨前肌和趾长伸肌（EDL）的质量显著降低。尽管转基因动物表现出合成代谢状态，但只有EDL完全免受消瘦。事实上，腓肠肌、胫骨前肌和比目鱼肌重量减轻，与非转基因荷瘤小鼠相比，后两者的消耗明显更多。同样，生殖器周围白色脂肪组织的质量减少，在转基因组中更明显。对EDL中泛素、E2、C8和钙蛋白酶基因表达的定量分析显示，肿瘤宿主的转基因组和非转基因组之间存在显著差异。正如先前结果所预期的那样, 在后者组中，由于肿瘤生长，大多数检测的转录本相对于对照组增加；相比之下，与无肿瘤的转基因动物相比，转基因荷瘤宿主中泛素、E2、C8亚基和钙蛋白酶mRNA水平显著降低。这些结果表明，c-ski的过度表达可能通过损害不同蛋白水解系统的激活状态来防止肿瘤诱导的EDL肌肉消瘦。然而，在所检查的其他肌肉中缺乏有效性表明，在分子水平上对恶病质发展实现显著干扰并非易事，可能需要考虑多个靶点来进行设计。
