Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72

Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1515-24. doi: 10.1152/ajpheart.00585.2010. Epub 2010 Sep 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Calcium / metabolism
  • Cardiotoxins / adverse effects*
  • Cardiotoxins / pharmacology
  • Doxorubicin / adverse effects*
  • Doxorubicin / pharmacology
  • HSP72 Heat-Shock Proteins / metabolism*
  • Lipid Peroxides / metabolism
  • Male
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / physiology*
  • Mitochondrial Diseases / chemically induced*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / prevention & control*
  • Models, Animal
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oxidative Stress / drug effects
  • Physical Conditioning, Animal / physiology*
  • Protein Isoforms / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism


  • Cardiotoxins
  • HSP72 Heat-Shock Proteins
  • Lipid Peroxides
  • Protein Isoforms
  • Reactive Oxygen Species
  • Doxorubicin
  • Calcium