Plasticidade mitocondrial no catabolismo muscular associado ao carcinoma urotelial: impacto do exercício físico
authors Paulo Jorge de Oliveira Laranjeira
supervisors Ana Isabel Martins Novais Padrão
thesis type MSc in Biochemistry (specialization in Clinical Biochemistry)
nationality International
author keywords cachexia, cancer, skeletal muscle, mitochondria, exercise
abstract Cancer cachexia is a multifactorial syndrome that presents a great challenge in clinical oncology. This syndrome is characterized by significant weight loss, mainly due to severe skeletal muscle wasting, which has a negative impact on quality of life, tolerance to treatment and life expectancy of patients. Mitochondrial dysfunction has been suggested as an early event associated with cancer induced muscle atrophy. Specifically, impaired mitochondrial turnover (biogenesis, dynamics and mitophagy), reduced ATP synthesis, higher levels of oxidative stress and higher susceptibility to apoptosis seem to compromise muscle contraction and promote catabolism associated with cancer cachexia. Recently, exercise training has been studied as a therapeutic approach due to its potentially beneficial effects in mitochondrial and muscle adaptation in cancer cachexia. In order to determine the impact of cancer and exercise training in skeletal muscle adaptation, an animal model of bladder cancer induced by exposure to BBN was submitted to 13 weeks of treadmill running after the establishment of the disease. Bladder cancer alone promoted a decrease in total body weight, suggesting the presence of cachexia. At the same time, a reduction in the cross sectional area of gastrocnemius muscle and an increase in interstitial fibrosis were noticed, suggesting an inflammatory profile and catabolism, which were attenuated by exercise training. Moreover, bladder cancer compromised oxidative phosphorylation in muscle mitochondria, reducing the levels of complex I and II OXPHOS subunits and causing impaired ATP synthesis. Mitochondrial biogenesis was reduced, evidenced by lower levels of PGC-1α and Tfam, without impact in (auto)mitophagy. Exercise training promoted the reestablishment of ATP synthesis and the expression of complex I and II OXPHOS subunits, as well as an increase in mitochondrial biogenesis markers (including Sirt3) and mitophagy (through Bnip3). Present data highlight the beneficial effects of endurance exercise on cancer cachexia-related muscle remodeling through the regulation of mitochondrial plasticity. As such, our data support the recommendation of physical activity to cancer patients for the management of cachexia.
year published 2016