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| Author(s): |
Luiz Roberto Grassmann Bechara
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Escola de Educação Física e Esportes (EEFE/BT) |
| Defense date: | 2012-12-04 |
| Examining board members: |
Paulo Rizzo Ramires;
Kátia de Angelis Lobo D\'Avila;
Francisco Rafael Martins Laurindo;
Alessandra Medeiros;
Carlos Eduardo Negrão
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| Advisor: | Patricia Chakur Brum; Paulo Rizzo Ramires |
| Abstract | |
Although heart failure (HF) is a syndrome of cardiac origin, it promotes significant skeletal muscle atrophy in more advanced stages, which contributes to poor prognosis and increased mortality rate. Reactive oxygen species (ROS) seem to be directly involved in the development and progression of muscle atrophy in chronic degenerative diseases. In fact, HF is associated with skeletal muscle oxidative stress, which seems to contribute to protein catabolism and muscle atrophy. However, it is important to highlight that the sources involved in the exacerbated skeletal muscle ROS production in HF have not been characterized yet. NADPH oxidase enzyme complex is an important source of ROS production activated by proinflammatory cytokines and some G-protein-coupled receptors, which are increased in HF. Therefore, in the first part of the thesis, we tested whether NADPH oxidases would be overactivated in plantaris and soleus muscles of rats submitted to myocardial infarction, thus contributing to oxidative stress and consequent ubiquitin proteasome proteolytic system (UPS) hyperactivation, ultimately leading to muscle atrophy. To test this hypothesis, Wistar rats underwent myocardial infarction or Sham surgery and, four weeks post-surgery, rats underwent eight weeks of treatment with an NADPH oxidase inhibitor (apocynin) or placebo. It was quantified in plantaris and soleus muscles: mRNA levels of skeletal muscle-NOX family, as well as NADPH oxidase activity; oxidative stress markers; antioxidant enzymes activity and total glutathione concentration; mRNA levels of UPS components and proteasome activity; and muscle trophicity (Subproject 1). In the second part of the thesis we tested whether aerobic exercise training (AET) would prevent NADPH oxidases overactivity in plantaris and soleus muscles of rats submitted to myocardial infarction, thus decreasing oxidative stress and UPS hyperactivation, preventing skeletal muscle atrophy. To test this hypothesis, Sham and infarcted rats underwent eight weeks of AET or remained sedentary (Subproject 2). The variables studied were the same as in Subproject 1. The results of the subproject 1 demonstrated that myocardial infarction in rats induces plantaris muscle atrophy triggered in part by overactivation of NADPH oxidase promoting increased ROS production paralleled by UPS hyperactivation. Moreover, myocardial infarction induced soleus muscle atrophy, which was also associated with increased ROS levels and proteasome overactivity, but independently of NADPH oxidase activation. Regarding the subproject 2, our data showed that AET partially prevented plantaris muscle atrophy in infarcted rats, preventing myocardial infarction-induced NADPH oxidase hyperactivation and UPS hyperactivation. AET also prevented soleus muscle atrophy in infarcted rats, which was associated with a ROS levels reduction and prevention of myocardial infarction-induced UPS hyperactivation, but independently of NADPH oxidase activity. Collectively, our data give support for the involvement of NADPH oxidase as a source of ROS production leading to UPS activation and skeletal muscle atrophy associated with chronic myocardial infarction, however this occurs in a muscle specific pattern. AET prevents myocardial infarction-induced skeletal muscle atrophy and exacerbated ROS levels in both plantaris and soleus muscles. In plantaris muscle, this response is related to a prevention of NADPH oxidase hyperactivation, highlighting the contribution of this enzyme complex to ROS production in glycolytic muscles of infarcted rats. Finally, AET is an important nonpharmacologic tool acting in skeletal muscle redox and protein homeostasis of infarcted rats (AU) | |