Int J Biochem Cell Biol. 2013 Jul;45(7):1399-409. doi: 10.1016/j.biocel.2013.04.014.

Bladder cancer-induced skeletal muscle wasting: disclosing the role of mitochondria plasticity.

Padrão AI, Oliveira P, Vitorino R, Colaço B, Pires MJ, Márquez M, Castellanos E, Neuparth MJ, Teixeira C, Costa C, Moreira-Gonçalves D, Cabral S, Duarte JA, Santos LL, Amado F, Ferreira R.

 

Abstract

Loss of skeletal muscle is a serious consequence of cancer as it leads to weakness and increased risk of death. To better understand the interplay between urothelial carcinoma and skeletal muscle wasting, cancer-induced catabolic profile and its relationship with muscle mitochondria dynamics were evaluated using a rat model of chemically induced urothelial carcinogenesis by the administration of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). The histologic signs of non-muscle-invasive bladder tumors observed in BBN animals were related to 17% loss of body weight and high serum levels of IL-1β, TNF-α, TWEAK, C-reactive protein, myostatin and lactate and high urinary MMPs activities, suggesting a catabolic phenotype underlying urothelial carcinoma. The 12% loss of gastrocnemius mass was related to mitochondrial dysfunction, manifested by decreased activity of respiratory chain complexes due to, at least partially, the impairment of protein quality control (PQC) systems involving the mitochondrial proteases paraplegin and Lon. This was paralleled by the accumulation of oxidatively modified mitochondrial proteins. In overall, our data emphasize the relevance of studying the regulation of PQC systems in cancer cachexia aiming to identify therapeutic targets to counteract muscle wasting.

Copyright © 2013 Elsevier Ltd.

PMID: 23608519

 

Supplement

Cachexia is a paraneoplasic syndrome that affects a large proportion of oncologic patients, compromising disease prognosis and therapeutic outcomes. The pathophysiology of cancer cachexia is complex and multifactorial, characterized by the loss of muscle with or without loss of fat mass. The identification of the molecular mechanisms underlying cancer-related muscle wasting may be useful for developing therapeutic approaches focused on avoiding or reducing body weight loss.

Using an animal model of chemically-induced bladder cancer that mimics the urothelium carcinogenesis process in humans, it was studied the alterations in the balance between catabolic and anabolic processes in the gastrocnemius muscle and the involvement of mitochondria in the regulation of muscle mass.

Animals with urothelial carcinoma presented a body weight loss of 17%, which was related to a decrease of 12% of gastrocnemius mass. Muscle wasting was explained, at least in part, by the activation of catabolic pathways mediated by myostatin, TWEAK and IL-1β cytokines and by the down-regulation of Akt/mTOR/S6K pathway. Concomitantly, it was noticed a lower ability of mitochondria to produce ATP, possibly due to the accumulation of oxidized proteins not prevented or eliminated by the mitochondrial protein quality control system.

The importance of tumor-related cytokines as players involved in muscle wasting is demonstrated, highlighting these proteins as potential therapeutic targets of cancer cachexia.

Rita Ferreira-fig1

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