The impact of doxorubicin and trastuzumab on the molecular remodeling of striated muscle

• Autor(a) principal: Anjos, Miguel Godinho de Oliveira
• Data de Publicação: 2020
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/30436
• topic: Cardiotoxicity; Doxorubicin; Trastuzumab; Skeletal muscle remodeling; Metabolism

In the last few decades, there has been a significant increase in the survival rate of cancer patients, mainly due to the use of ever-improving treatment modalities, such as chemotherapy and immunotherapy. However, the use of these treatments, such as the ones involving doxorubicin and trastuzumab, have been accompanied by severe toxicity, especially with serious cardiac toxicity. To better understand the toxicity induced by doxorubicin plus trastuzumab, in the first part of this thesis, it is presented a review integrating the molecular mechanisms harbored in the different cardiac cell types and regulated by these therapeutic approaches. This analysis emphasizes the involvement of ROS and HER2 signaling in the damaging effect of this combined treatment, but other pathways intervene. In addition to cardiotoxicity, doxorubicin may also impact skeletal muscle function, consequently affecting the quality of life of cancer patients. Thus, to better understand the toxicity induced by doxorubicin in skeletal muscle, adult male mice were exposed to treatment with doxorubicin for 3 weeks (cumulative dose of 9mg/Kg or 18mg/Kg). At the end of the protocol, soleus and gastrocnemius muscles were collected. Our study focused on the molecular remodeling of the soleus muscle since macroscopic signs of atrophy induced by doxorubicin were observed. The biochemical analysis focused on the effect of doxorubicin on soleus metabolic adaptations and regulatory mechanisms involved. Data revealed a significant increase in GAPDH and PFK1 levels, after doxorubicin administration, indicating a metabolic shift in favor of glycolysis for energetic purposes. This metabolic adaptation was not accompanied by changes in mitochondrial dynamics and in the regulation of ubiquitin-proteasome pathway. In conclusion, our study shows that doxorubicin treatment in mice promotes the remodeling of soleus muscle, mainly at the metabolic level; however, more pathways should be evaluated to better comprehend the molecular adaptations promoted by doxorubicin in skeletal muscle and their functional impact.