Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis.
The objective of this work was to test the hypothesis that endurance training may be protective against in vivo doxorubicin (DOX)-induced cardiomyopathy through mitochondria-mediated mechanisms. Forty adult (6-8 wk old) male Wistar rats were randomly divided into four groups (n = 10/group): nontrained, nontrained + DOX treatment (20 mg/kg), trained (14 wk of endurance treadmill running, 60-90 min/day), and trained + DOX treatment. Mitochondrial respiration, calcium tolerance, oxidative damage, heat shock proteins (HSPs), antioxidant enzyme activity, and apoptosis markers were evaluated. DOX induces mitochondrial respiratory dysfunction, oxidative damage, and histopathological lesions and triggers apoptosis (P < 0.05, n = 10). However, training limited the decrease in state 3 respiration, respiratory control ratio (RCR), uncoupled respiration, aconitase activity, and protein sulfhydryl content caused by DOX treatment and prevented the increased sensitivity to calcium in nontrained + DOX-treated rats (P < 0.05, n = 10). Moreover, training inhibited the DOX-induced increase in mitochondrial protein carbonyl groups, malondialdehyde, Bax, Bax-to-Bcl-2 ratio, and tissue caspase-3 activity (P < 0.05, n = 10). Training also increased by approximately 2-fold the expression of mitochondrial HSP-60 and tissue HSP-70 (P < 0.05, n = 10) and by approximately 1.5-fold the activity of mitochondrial and cytosolic forms of SOD (P < 0.05, n = 10). We conclude that endurance training protects heart mitochondrial respiratory function from the toxic effects of DOX, probably by improving mitochondrial and cell defense systems and reducing cell oxidative stress. In addition, endurance training limited the DOX-triggered apoptosis.
Ascensão
António
A
Department of Sport Biology, Faculty of Sport Sciences, Univ. of Porto, Rua Dr. Plácido Costa, 91, 4200-450 Porto, Portugal. aascensao@fcdef.up.pt
Magalhães
José
J
Soares
José M C
JM
Ferreira
Rita
R
Neuparth
Maria J
MJ
Marques
Franklim
F
Oliveira
Paulo J
PJ
Duarte
José A
JA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000517:prevention & control*; D004317:Doxorubicin / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D051381:Rats; D017208:Rats, Wistar
D004317:Doxorubicin