Efeitos protetores do treinamento resistido sobre a miotoxicidade induzida pela doxorrubicina em ratos

Abstract

Doxorubicin (Dox) is a highly effective chemotherapy drug from the anthracycline class that is associated with a multitude of serious adverse effects, including myotoxicity. The objective of the present study is to investigate whether resistance training (RT) can attenuate Dox-induced skeletal muscle toxicity in rats by modulating the expression of proteins involved in protein balance, apoptosis, mitochondrial biogenesis and possible participation of the renin- angiotensin system. Furthermore, check whether possible changes differ between skeletal muscles. Male adults Sprague Dawley rats were randomly divided into Control (NaCl/sedentary, n=10), Dox/Sed (Dox/sedentary, n=16), or Dox/RT (Dox/endurance-trained) groups (n=16). Dox or saline were administered for 10 days (1 mg/kg/d, i.p.). RT consisted of climbing a ladder apparatus with 54 steps with overload (15 repetitions/d; 5 days/week; 20 to 60% of maximum load; for 8 weeks). After euthanasia, skeletal muscles soleus and gastrocnemius were dissected and processed for microscopy or frozen for Western blot. RT reduced mortality, weight loss, and improved overall strength compared to Dox/Sed. Dox/Sed rats exhibited significantly lower myocyte cross-sectional area of both soleus and gastrocnemius compared to Control and Dox/RT. Furthermore, RT mitigated the ultrastructural damage to skeletal muscles caused by Dox. Electron micrographs of both muscles of Dox/RT animals showed many fields with regularly arranged myofibrils and sarcomeres, preserved mitochondria and absence of organelles that suggest protein degradation; in opposition to the conclusions of the Dox/Sed group. These changes were accompanied by greater Catalase activity compared to the Dox/RT group and lower GPx activity compared to the Control. However, the TR was able to reverse this situation. Dox/Sed group showed greater protein damage compared to the Control. Furthermore, Dox reduced protein levels of Akt and p- AktSer473, but their relationship did not differ between groups. In the gastrocnemius, Rab 7 expression was higher in the Dox/Sed group than in the Control group, while ACE2 was higher in the Dox/RT group than in the Dox/Sed group. In the soleus, cytochrome C expression was reduced in the Dox/RT group compared to the Dox/Sed group. Furthermore, PGC1-α expression was reduced in the Dox/Sed group compared to the Control group. However, RT was able to increase its expression. Protein levels of ACE2 were reduced in the groups treated with Dox, however, we observed that RT increased the protein levels of the ACE/ECA2 ratio, which were reduced in the Dox/Sed group. The expression of p-P70S6KThr389, MuRF-1, Atrogin-1, Caspase-3, AT1R, MasR, ACE, bradykinin receptors, IL-6 and TNF-α was similar between groups in both muscles. RT mitigated Dox-derived myotoxicity, it was effective in attenuating mortality, preserving the ultrastructure of skeletal muscles, preventing atrophy of both muscles, accompanied by a reduction in the ACE/ACE2 ratio and a reduction in pNFκB. Furthermore, it was able to increase the expression of the protein involved in mitochondrial biogenesis. RT performed during Dox treatment may be a valuable approach to mitigate associated muscle damage.