Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats

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.

Effects of the beta 2 agonist formoterol on atrophy signaling, autophagy, and muscle phenotype in respiratory and limb muscles of rats with cancer-induced cachexia

“…The Yoshida AH-130 ascites hepatoma is a suitable approach to study the underlying biological events of muscle wasting in cancer-induced cachexia, as already demonstrated in several investigations [10][11][12][26][27][28]51]. In the study, expression levels of activated NF-κB p65 and FoxO3 were significantly increased in both respiratory and limb muscles.…”

“…Protein levels of the different molecular markers analyzed in the study were explored by means of immunoblotting procedures as previously described [14][15][16][17][18]25,45,46,50,51].…”

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

“…By contrast, a preclinical study has shown that cachexia induced in the host rat by the AH-130 tumor leads to distinct responses in locomotor and respiratory muscles, the former being more susceptible to oxidative stress than the latter, despite the increase of the endogenous antioxidant defense (115), likely due to an ineffective adaptive response. Similarly, increased pro-oxidant species coupled with the activation of the antioxidant defense has been reported in the muscle of C26-bearing mice (6,12).…”

Muscle Phenotype, Proteolysis, and Atrophy Signaling During Reloading in Mice: Effects of Curcumin on the Gastrocnemius

“…As such, in models of disuse muscle atrophy and wasting, a rise in the levels of markers of proteolysis, autophagy, apoptosis, oxidative stress, and epigenetic modifications have been shown in muscles of both patients [2,[6][7][8][9][10][11] and animals [12][13][14][16][17][18][19][20][21][22]. Additionally, alterations in the structure of the myofibers along with a reduction in their size have also been demonstrated in muscles following periods of inactivity [12][13][14][16][17][18][19][20][21][22].The study of the kinetics of the pathophysiological and biological events whereby the loss of muscle mass takes place following periods of disuse is important [23][24][25]. In this regard, the sequence of the expression of markers of proteolysis, apoptosis, autophagy, signaling, of structural alterations and fiber type switches, and that of impaired function have already been described in previous investigations [23][24][25].Post-translational modifications of transcription factors that signal proteolytic activation in muscles were described in several models of muscle atrophy [24][25][26].…”