Biochemical and molecular mechanisms of cachexia. effects of Walker factor and leucine supplementation on myotube cell culture

Abstract

Patients with cancer lose weight and often suffer of cachexia state. It is not known precisely how or why cancer so frequently develops in such a way as to induce cachexia. In patients with cancer-cachexia, there is an intense mobilization of carcass substrates occurring preferentially depletion in muscle protein due to reduced synthesis and / or increased protein degradation. Protein catabolism is also related to lysosomal and calcium-dependent pathway. Although, the main system of weight loss induced by cancer is the ubiquitin-proteasome pathway, the main route of degradation of specific proteins, such as contractile skeletal muscle, in the presence of cancer. The increase in the expression of ubiquitin-proteasome pathway can be attributed to proteolysis inducing factor (PIF) produced by the tumor. The main interest is to investigate the molecular mechanism of cell signaling, particularly in skeletal muscle, which occurs during the cancer cachexia process under the effects of leucine supplementation. Leucine is able to attenuate protein degradation in skeletal muscle by preventing the increased expression of the ubiquitin-proteasome and also stimulating the process of protein synthesis, which is often inhibited during cancer-cachexia. Recently, we have isolated and purified a protein with the same molecular weight as 24kDa, from ascites fluid of Walker tumour-bearing rats, and we named as Walker factor (FW). The FW has the same detrimental effects as the proteolysis-inducing factor (PIF), therefore the study of its effects in experimental models is so important. Thus, this project aims to assess the biochemical and molecular mechanisms involved in protein synthesis and degradation effects produced by Walker Factor under modulatory effect of leucine supplementation in skeletal muscle cells (C2C12). The importance of this project is to contribute the greater understanding of cell signaling for protein synthesis and degradation. These findings can allow the analogy imposed by the neoplastic growth mainly to the muscle undergoing the leucine nutritional supplementation. (AU)