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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)

Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CRUZ, BREAD; OLIVEIRA, ANDRE; VENTRUCCI, GISLAINE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. A leucine-rich diet modulates the mTOR cell signalling pathway in the gastrocnemius muscle under different Walker-256 tumour growth conditions. BMC CANCER, v. 19, APR 11 2019. Web of Science Citations: 0.
DA SILVA MIYAGUTI, NATALIA ANGELO; PEREIRA DE OLIVEIRA, SARAH CHRISTINE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Maternal nutritional supplementation with fish oil and/or leucine improves hepatic function and antioxidant defenses, and minimizes cachexia indexes in Walker-256 tumor-bearing rats offspring. Nutrition Research, v. 51, p. 29-39, MAR 2018. Web of Science Citations: 2.
FAVERO-SANTOS, BIANCA CRISTINE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Leucine can modulate the expression of proteins related to protein degradation signalling under mTOR inhibition in C2C12 cells. Cellular & Molecular Biology, v. 64, n. 10, p. 73-78, 2018. Web of Science Citations: 0.
CRUZ, BREAD; OLIVEIRA, ANDRE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. L-leucine dietary supplementation modulates muscle protein degradation and increases pro-inflammatory cytokines in tumour-bearing rats. CYTOKINE, v. 96, p. 253-260, AUG 2017. Web of Science Citations: 7.
TONETO, ALINE TATIANE; FERREIRA RAMOS, LUIZ ALBERTO; SALOMAO, EMILIANNE MIGUEL; TOMASIN, REBEKA; AEREAS, MIGUEL ARCANJO; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 7, n. 5, p. 577-586, DEC 2016. Web of Science Citations: 16.
VIANA, LAIS ROSA; CANEVAROLO, RAFAEL; PERINA LUIZ, ANNA CAROLINE; SOARES, RAQUEL FRIAS; LUBACZEUSKI, CAMILA; DE MATTOS ZERI, ANA CAROLINA; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Leucine-rich diet alters the H-1-NMR based metabolomic profile without changing the Walker-256 tumour mass in rats. BMC CANCER, v. 16, OCT 3 2016. Web of Science Citations: 8.
OLIVEIRA, ANDRE G.; GOMES-MARCONDES, MARIA CRISTINA C. Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats. BMC CANCER, v. 16, JUL 7 2016. Web of Science Citations: 17.
GOMES CRUZ, BREAD LEANDRO; DA SILVA, PRISCILA CRISTINA; TOMASIN, REBEKA; OLIVEIRA, ANDRE GUSTAVO; VIANA, LAIS ROSA; SALOMAO, EMILIANNE MIGUEL; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Dietary leucine supplementation minimises tumour-induced damage in placental tissues of pregnant, tumour-bearing rats. BMC CANCER, v. 16, FEB 4 2016. Web of Science Citations: 4.
TOMASIN, REBEKA; DE ANDRADE, RAFAEL SIQUEIRA; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Oral Administration of Aloe vera (L.) Burm. f. (Xanthorrhoeaceae) and Honey Improves the Host Body Composition and Modulates Proteolysis Through Reduction of Tumor Progression and Oxidative Stress in Rats. JOURNAL OF MEDICINAL FOOD, v. 18, n. 10, p. 1128-1135, OCT 1 2015. Web of Science Citations: 3.

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