title: Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress.
abstract: Doxorubicin (DOX) is an anti-cancer agent whose clinical usage results in a cumulative and dose-dependent cardiotoxicity. We have previously shown that exercise performed prior to DOX treatment reduces the resulting cardiac(mito) toxicity. We sought to determine the effects on cardiac mitochondrial toxicity of two distinct chronic exercise models (endurance treadmill training-TM and voluntary free-wheel activity-FW) when used prior and during DOX treatment. Male-young Sprague-Dawley rats were divided into six groups (n=6 per group): SAL+SED (saline sedentary), SAL+TM (12-weeks TM), SAL+FW (12-weeks FW), DOX+SED (7-weeks of chronic DOX treatment 2mg/kg per week), DOX+TM and DOX+FW. DOX administration started 5weeks after the beginning of the exercise protocol. Heart mitochondrial ultrastructural alterations, mitochondrial function (oxygen consumption and membrane potential), semi-quantification of oxidative phosphorylation (OXPHOS) proteins and their in-gel activity, as well as proteins involved in mitochondrial oxidative stress (SIRT3, p66shc and UCP2), biogenesis (PGC1α and TFAM), acetylation and markers for oxidative damage (carbonyl groups, MDA,SH, aconitase, Mn-SOD activity) were evaluated. DOX treatment resulted in ultrastructural and functional alterations and decreased OXPHOS. Moreover, DOX decreased complex I activity and content, mitochondrial biogenesis (TFAM), increased acetylation and oxidative stress. TM and FW prevented DOX-induced alteration in OXPHOS, the increase in oxidative stress, the decrease in complex V activity and in complex I activity and content. DOX-induced decreases in TFAM and SIRT3 content were prevented by TM only. Both chronic models of physical exercise performed before and during the course of sub-chronic DOX treatment translated into an improved mitochondrial bioenergetic fitness, which may result in part from the prevention of mitochondrial oxidative stress and damage.
authors.affiliation: CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal. Electronic address: inesmaleixo@hotmail.com.
authors.forename: Inês
authors.initials: I
authors.lastname: Marques-Aleixo
authors.affiliation: CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal; CNC - Centre for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Estela
authors.initials: E
authors.lastname: Santos-Alves
authors.affiliation: CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal.
authors.forename: Diogo
authors.initials: D
authors.lastname: Mariani
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Rizo-Roca
authors.affiliation: QOPNA Chemistry Department, University of Aveiro, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Padrão
authors.affiliation: CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Rocha-Rodrigues
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Spain.
authors.forename: Ginés
authors.initials: G
authors.lastname: Viscor
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Spain.
authors.forename: J Ramon
authors.initials: JR
authors.lastname: Torrella
authors.affiliation: QOPNA Chemistry Department, University of Aveiro, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
authors.affiliation: CNC - Centre for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
authors.affiliation: CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Magalhães
authors.affiliation: CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Ascensão
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D054715:Cardiotoxins / Q000008:administration & dosage / Q000009:adverse effects*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D004734:Energy Metabolism; D006801:Humans; D008297:Male; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D017207:Rats, Sprague-Dawley
chemical_list: D000903:Antibiotics, Antineoplastic; D054715:Cardiotoxins; D004317:Doxorubicin
keywords: Adriamycin; Bioenergetics; Cardioprotection; Exercise; Oxidative damage