Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress
Introduction
Doxorubicin (DOX, or adriamycin) is an effective antibiotic used to treat several malignancies. Unfortunately, its clinical use is limited by the development of a dose-dependent cardiac toxicity that results in life-threatening cardiomyopathy. DOX-induced cardiomyocyte dysfunction is associated with increased levels of oxidative damage with the involvement of mitochondrial bioenergetic collapse in the process (Wallace, 2007). In fact, sub-chronic DOX-treated rats show defects on heart mitochondrial function, accompanied by compromised mitochondrial electron transport chain activity and increased oxidative stress and damage (Abd El-Gawad and El-Sawalhi, 2004, Berthiaume et al., 2005, Santos et al., 2002).
Among the strategies proposed as effective in counteracting the cardiac side effects associated with DOX treatment, physical exercise has been recommended as a non-pharmacological tool against myocardial injury (Ascensao et al., 2006c, Ascensao et al., 2007, Ascensao et al., 2011b, Powers et al., 2008). Previous work suggested that the advantage of both acute (Ascensao et al., 2011a, Wonders et al., 2008) and chronic exercise models (Ascensao et al., 2005a, Ascensao et al., 2005b, Ascensao et al., 2006a, Chicco et al., 2005, Chicco et al., 2006, Dolinsky et al., 2013) on triggering a preconditioning-like effect on DOX-treated rats with acute single doses includes the protection of cardiac tissue and especially mitochondria against negative remodeling. Recent studies investigated the effects of exercise performed during and following late-onset DOX-induced cardiotoxicity which showed improvements in hemodynamic parameters (Hayward et al., 2012, Hydock et al., 2012a). However, the cellular and molecular mechanisms underlying this protective phenotype induced by exercise against sub-chronic DOX administration, particularly those targeting mitochondria, are unknown. Specifically, whether perturbations in heart mitochondrial oxidative phosphorylation capacity and oxidative modifications associated with sub-chronic cumulative DOX administration are mitigated by “forced” or “voluntary” long-term exercise models performed prior and during the course of treatments have not been determined and represents the novelty of the present study. As patients undergoing chemotherapy experience severe fatigue and display severe exercise intolerance, the intensity and duration of tolerable exercise are likely to be severely limited (Emter and Bowles, 2008). Facing this, we aimed at analyzing the effects of two types of long-term exercise with distinct characteristics regarding volume and intensity on cardiac mitochondrial bioenergetics and oxidative stress markers in rats sub-chronically treated with DOX.
Section snippets
Animals
All experimental procedures were conducted in accordance with the Directive 2010/63/EU of the European Parliament and were approved by the Ethics Committee of the Research Centre in Physical Activity, Heath and Leisure (Faculty of Sport, University of Porto). Thirty-six male 6-weeks old Sprague–Dawley rats were housed in individual cages in 12 h light/dark cycles with free access to food and water.
Animals were randomly divided into six groups (n = 6 per group): saline sedentary (SAL + SED), saline
Results
Heart weight, mitochondrial protein isolation yield as well as the activity of soleus citrate synthase and cTnI are shown in Table 1. As expected, heart weight decreased with DOX treatment (SAL + SED vs. DOX + SED) and TM and FWinduced heart hypertrophy (SAL + TM and SAL + FW vs. SAL + SED and DOX + TM and DOX + FW vs. DOX + SED). TM increased soleus citrate synthase activity in both SAL and DOX-treated animals (SAL + SED vs. SAL + TM and DOX + SED vs. DOX + TM).
Body mass alterations and distances covered by the
Discussion
The main finding of the present study was that TM and FW, performed before and during the course of sub-chronic DOX treatment, prevented mitochondrial dysfunction and regulated oxidative stress. Our objective was to find out whether any of these exercise models was effective in counteracting cardiac mitochondrial structural alterations, compromised mitochondrial biogenesis, oxidative damage and bioenergetic disruption caused by cumulative sub-chronic DOX treatment. The present study
Acknowledgments
This work was supported by the Portuguese Foundation for Science and Technology (FTC) grants as follows: SFRH/BDP/4225/2007, PTDC/DTP-DES/1071/2012-FCOMP-01-0124-FEDER-028618 and PP_IJUP2011_253 to AA, SFRH/BPD/66935/2009 to JM, SFRH/BD/61889/2009 to IMA, SFRH/BD/89807/2012 to SR, PTDC/SAU-TOX/110952/2009, PTDC/SAU-TOX/117912/2010 and PTDC/DTP-FTO/1180/2012 to PJO, Pest-C/SAU/LA0001/2013-2014 to CNC and PEst-OE/SAU/UI0617/2011 to CIAFEL. DRR is supported by Muscletech Network (MTN20100101) and
References (58)
- et al.
Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice
Int. J. Cardiol.
(2005) - et al.
Endurance training limits the functional alterations of rat heart mitochondria submitted to in vitro anoxia-reoxygenation
Int. J. Cardiol.
(2006) - et al.
Exercise-induced cardioprotection—biochemical, morphological and functional evidence in whole tissue and isolated mitochondria
Int. J. Cardiol.
(2007) - et al.
The SirT3 divining rod points to oxidative stress
Mol. Cell
(2011) - et al.
Isolation of skeletal muscle mitochondria from hamsters using an ionic medium containing ethylenediaminetetraacetic acid and nagarse
Anal. Biochem.
(1991) - et al.
Effect of adriamycin on electron transport in rat heart, liver, and tumor mitochondria
Exp. Mol. Pathol.
(1987) - et al.
Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3
Mitochondrion
(2013) - et al.
Microsomal lipid peroxidation
Methods Enzymol.
(1978) - et al.
Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase
J. Biol. Chem.
(1986) - et al.
Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical
J. Biol. Chem.
(1986)