title: Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats.
abstract: The use of DOX (doxorubicin), an antibiotic used in oncological treatments, is limited by a dose-related cardiotoxicity against which acute exercise is protective. However, the mitochondrial-related mechanisms of this protection remain unknown. Therefore the present study aimed to determine the effects of an acute endurance exercise bout performed 24 h before DOX treatment on heart and liver mitochondrial function. A total of 20 adult male Wistar rats were divided into groups as follows: non-exercised with saline (NE + SAL), non-exercised DOX-treated (NE + DOX), exercised with saline (EX + SAL) and exercised DOX-treated (EX + DOX). The animals performed a 60 min exercise bout on a treadmill or remained sedentary 24 h before receiving either a DOX bolus (20 mg/kg of body weight) or saline. Heart and liver mitochondrial function [oxygen consumption, membrane potential (DeltaPsi) and cyclosporin-A-sensitive calcium-induced MPTP (mitochondrial permeability transition pore) opening] were evaluated. The activities of the respiratory complex, Mn-SOD (superoxide dismutase), caspases 3 and 9, as well as the levels of ANT (adenine nucleotide translocase), VDAC (voltage-dependent anion channel), CypD (cyclophilin D), Bax and Bcl-2, were measured. Acute exercise prevented the decreased cardiac mitochondrial function (state 3, phosphorylative lagphase; maximal DeltaPsi generated both with complex I- and II-linked substrates and calcium-induced MPTP opening) induced by DOX treatment. Exercise also prevented the DOX-induced decreased activity of cardiac mitochondrial chain complexes I and V, and increased caspase 3 and 9 activities. DOX administration and exercise caused increased cardiac mitochondrial SOD activity. Exercise ameliorated liver mitochondrial complex activities. No alterations were observed in the measured MPTP and apoptosis-related proteins in heart and liver mitochondria. The results demonstrate that acute exercise protects against cardiac mitochondrial dysfunction, preserving mitochondrial phosphorylation capacity and attenuating DOX-induced decreased tolerance to MPTP opening.
authors.affiliation: Research Centre in Physical Activity, Health and Leisure, Faculty of Sport Sciences, University of Porto, 4200-450 Porto, Portugal. aascensao@fcdef.up.pt
authors.forename: António
authors.initials: A
authors.lastname: Ascensão
authors.forename: José
authors.initials: J
authors.lastname: Lumini-Oliveira
authors.forename: Nuno G
authors.initials: NG
authors.lastname: Machado
authors.forename: Rita M
authors.initials: RM
authors.lastname: Ferreira
authors.forename: Inês O
authors.initials: IO
authors.lastname: Gonçalves
authors.forename: Ana C
authors.initials: AC
authors.lastname: Moreira
authors.forename: Franklin
authors.initials: F
authors.lastname: Marques
authors.forename: Vilma A
authors.initials: VA
authors.lastname: Sardão
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
authors.forename: José
authors.initials: J
authors.lastname: Magalhães
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009043:Motor Activity / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D017494:Proton Pumps / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017494:Proton Pumps; D004317:Doxorubicin; D013482:Superoxide Dismutase; D002118:Calcium