Aerobic exercise training attenuates doxorubicin-induced ultrastructural changes in rat ventricular myocytes

Aims To investigate the effects of aerobic exercise training on cardiomyocyte ultrastructure, oxidative stress, and activation of protein synthesis pathways in a model of cardiomyopathy induced by doxorubicin (Dox). Main methods Male Sprague Dawley rats were randomly assigned to Control (saline, sedentary), Dox/sedentary (DoxSed), or Dox/exercise (DoxEx) groups. Saline or Dox were injected i.p. for 10 days (1 mg/kg/d). Aerobic exercise training was performed for 9 wks (starting with drug administration) on a treadmill, 5 d/wk, 30 min/d at 60% of maximum velocity. After euthanasia, the left ventricle (LV) was dissected, and processed for microscopy or frozen for Western blot and kinetic measurement of antioxidant enzymes activity. Key findings Dox resulted in a mortality of 31.2% of sedentary animals, whilst all animals from both Control and DoxEx groups survived. DoxSed animals presented increased LV connective tissue deposition alongside with massive sarcomeric disorganization with dissolution of myofibrils and wavy Z-lines. There was an increase in oxidative damage and a reduction in the activation of both Akt and ERK pathways in LV from DoxSed compared to Control group. Aerobic training caused notable changes in myocardial structure with reduced fibrosis and preservation of myofibrils integrity and sarcomere organization. This was associated with reduced LV oxidative damage and increased activity of antioxidant enzymes, and an increase in the activation of PI3K-Akt pathway. Significance Aerobic exercise training was effective in preventing mortality caused by Dox and in preserving LV ultrastructure, partially via activation of the physiological protein synthesis pathway, PI3K-Akt, and reducing oxidative stress.