title: Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72.
abstract: Doxorubicin (Dox) is an antitumor agent used in cancer treatment, but its clinical use is limited due to cardiotoxicity. Although exercise training can defend against Dox-mediated cardiac damage, the means for this cardioprotection remain unknown. To investigate the mechanism(s) responsible for exercise training-induced cardioprotection against Dox-mediated cardiotoxicity, we tested a two-pronged hypothesis: 1) exercise training protects against Dox-induced cardiotoxicity by preventing Dox-mediated mitochondrial damage/dysfunction and increased oxidative stress and 2) exercise training-induced cardiac expression of the inducible isoform of the 70-kDa heat shock protein 72 (HSP72) is essential to achieve exercise training-induced cardioprotection against Dox toxicity. Animals were randomly assigned to sedentary or exercise groups and paired with either placebo or Dox treatment (i.e., 20 mg/kg body wt ip Dox hydrochloride 24 h before euthanasia). Dox administration resulted in cardiac mitochondrial dysfunction, activation of proteases, and apoptosis. Exercise training increased cardiac antioxidant enzymes and HSP72 protein abundance and protected cardiac myocytes against Dox-induced mitochondrial damage, protease activation, and apoptosis. To determine whether exercise-induced expression of HSP72 in the heart is required for this cardioprotection, we utilized an innovative experimental strategy that successfully prevented exercise-induced increases in myocardial HSP72 levels. However, prevention of exercise-induced increases in myocardial HSP72 did not eliminate the exercise-induced cardioprotective phenotype that is resistant to Dox-mediated injury. Our results indicate that exercise training protects against the detrimental side effects of Dox in cardiac myocytes, in part, by protecting mitochondria against Dox-mediated damage. However, this exercise-induced cardioprotection is independent of myocardial HSP72 levels. Finally, our data are consistent with the concept that increases in cardiac mitochondrial antioxidant enzymes may contribute to exercise-induced cardioprotection.
authors.affiliation: Applied Physiology and Kinesiology, University of Florida, USA. ak771@msstate.edu
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kavazis
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Smuder
authors.forename: Kisuk
authors.initials: K
authors.lastname: Min
authors.forename: Nihal
authors.initials: N
authors.lastname: Tümer
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D054715:Cardiotoxins / Q000009:adverse effects* / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010805:Physical Conditioning, Animal / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D054715:Cardiotoxins; D050884:HSP72 Heat-Shock Proteins; D008054:Lipid Peroxides; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D002118:Calcium