Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72
- 1 November 2010
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 299 (5), H1515-H1524
- https://doi.org/10.1152/ajpheart.00585.2010
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.Keywords
This publication has 48 references indexed in Scilit:
- Exercise Preconditioning of the MyocardiumSports Medicine, 2009
- Exercise training induces a cardioprotective phenotype and alterations in cardiac subsarcolemmal and intermyofibrillar mitochondrial proteinsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2009
- Mechanical ventilation induces diaphragmatic mitochondrial dysfunction and increased oxidant productionFree Radical Biology & Medicine, 2009
- Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuliAmerican Journal of Physiology-Heart and Circulatory Physiology, 2008
- Exercise-induced cardioprotection against myocardial ischemia–reperfusion injuryFree Radical Biology & Medicine, 2007
- Endurance training limits the functional alterations of heart rat mitochondria submitted to in vitro anoxia-reoxygenationInternational Journal of Cardiology, 2006
- Cardiac Myocyte Apoptosis Is Associated With Increased DNA Damage and Decreased Survival in Murine Models of ObesityCirculation Research, 2006
- Endurance training attenuates doxorubicin-induced cardiac oxidative damage in miceInternational Journal of Cardiology, 2005
- Doxorubicin treatment in vivo activates caspase‐12 mediated cardiac apoptosis in both male and female ratsFEBS Letters, 2004
- Exercise, heat shock proteins, and myocardial protection from I-R injuryMedicine & Science in Sports & Exercise, 2001