Effect of c-ski overexpression on the development of cachexia in mice bearing the Lewis lung carcinoma.

Abstract

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.