ROLE OF TNF RECEPTOR-1 IN PROTEIN-TURNOVER DURING CANCER CACHEXIA USING GENE KNOCKOUT MICE

The implantation of the Lewis lung carcinoma (a fast-growing mouse tum our that induces cachexia) to both wild-type and gene-deficient mice f or the TNF-alpha receptor type I protein (Tnfr1 degrees/Tnfr1 degrees) , resulted in a considerable loss of carcass weight in both groups. Ho wever, while in the wild-type mice there was a loss of both fat and mu scle, in the gene-knockout mice muscle wastage was not affected to the same extent. In both groups, tumour burden resulted in significant in creases in circulating TNF-alpha, a cytokine which, as we have previou sly demonstrated, can induce protein breakdown in skeletal muscle. Mus cle wastage in wild-type mice was accompanied by an increase in the fr actional rate of protein degradation, while no changes were observed i n protein synthesis. The result is a decreased rate of protein accumul ation that accounts for the muscle weight loss observed as a result of tumour burden. In contrast, gene knockout mice did not have significa ntly lower rates of protein accumulation as a result of tumour implant ation. The increase in protein degradation in the tumour-bearing wild mice was accompanied by an enhanced expression of both ubiquitin and p roteasome subunit genes, all of them related to the activation of the ATP-dependent proteolytic system in skeletal muscle. Tumour-bearing ge ne-deficient mice did not show any increase in gene expression. It is concluded that TNF-alpha (alone or in combination with other cytokines ) is responsible for the activation of protein breakdown in skeletal m uscle of tumour-bearing mice. (C) 1998 Elsevier Science Ireland Ltd. A ll rights reserved.