Abstract
Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection), redox balance (protein oxidation and nitration and antioxidants) and muscle proteins (1-dimensional immunoblots), carbonylated proteins (2-dimensional immunoblots), inflammatory cells (immunohistochemistry), and mitochondrial respiratory chain (MRC) complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV). Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius.
Highlights
The analysis of the diaphragm muscle, which must remain continuously active, has been included as most of the investigations published so far have mainly focused on the evaluation of the peripheral muscles. Such an approach enabled us to identify whether the activity of the muscle influenced the profile of biological events. Taking all this into consideration, in the study, we focused on the analysis of diaphragm and gastrocnemius of cachectic rats bearing the Yoshida ascites hepatoma (Busquets et al, 2004; Busquets et al, 2011; Busquets et al, 2012; Fontes-Oliveira et al, 2013; Fontes-Oliveira et al, 2014; Toledo et al, 2011; Toledo et al, 2016), and the following biological events were analyzed in response to treatment with formoterol: (1) oxidative stress markers, antioxidants, and activity of mitochondrial complexes of the respiratory chain, (2) inflammatory cells, and (3) levels of intramuscular specific muscle proteins known to be oxidized in muscles
The weights of diaphragm and gastrocnemius muscles were significantly smaller in cancer-cachexia rats than in non-cachexia controls, and treatment with formoterol elicited a significant improvement in the weight of these muscles in the cachectic animals (Table 1)
We previously demonstrated that levels of carbonylation of MyHC protein were significantly greater in diaphragm (Marin-Corral et al, 2009; Salazar-Degracia et al, 2016) and limb muscles (Fermoselle et al, 2012; Puig-Vilanova et al, 2014c) of patients with advanced chronic obstructive pulmonary disease (COPD) than those detected in the controls
Summary
Muscle mass loss and wasting are characteristic features of patients with chronic conditions such as chronic heart failure, diabetes, renal failure, chronic obstructive pulmonary disease (COPD), cancer, and critical illness (Alvarez et al, 2016; Barreiro et al, 2015; Barreiro, 2017; Diaz, Ospina-Tascon & Salazar, 2014; Evans et al, 2008; Fearon et al, 2011; Villar et al, 2016; Von & Anker, 2010) Cachexia is characterized by severe body weight and muscle loss together with alterations in metabolic parameters. Oxidative stress, defined as the imbalance between oxidants and antioxidants in favor of the former, has been implicated in the pathogenesis of several conditions including chronic disease-associated muscle wasting and cachexia (Barreiro et al, 2003; Barreiro et al, 2008; Barreiro et al, 2010; Barreiro et al, 2011; Barreiro, 2017; Fermoselle et al, 2012; Marin-Corral et al, 2009; Marin-Corral et al, 2010; Puig-Vilanova et al, 2014c).
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