title: Physical exercise mitigates doxorubicin-induced brain cortex and cerebellum mitochondrial alterations and cellular quality control signaling.
abstract: Doxorubicin (DOX) is a highly effective anti-neoplastic agent, whose clinical use is limited by a dose-dependent mitochondrial toxicity in non-target tissues, including the brain. Here we analyzed the effects of distinct exercise modalities (12-week endurance treadmill-TM or voluntary free-wheel activity-FW) performed before and during sub-chronic DOX treatment on brain cortex and cerebellum mitochondrial bioenergetics, oxidative stress, permeability transition pore (mPTP), and proteins involved in mitochondrial biogenesis, apoptosis and auto(mito)phagy. Male Sprague-Dawley rats were divided into saline-sedentary (SAL+SED), DOX-sedentary (DOX+SED; 7-week DOX (2 mg · kg(-1)per week)), DOX+TM and DOX+FW. Animal behavior and post-sacrifice mitochondrial function were assessed. Oxidative phosphorylation (OXPHOS) subunits, oxidative stress markers or related proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn-SOD), as well as proteins involved in mitochondrial biogenesis (PGC1α and TFAM) were evaluated. Apoptotic signaling was followed through caspases 3, 8 and 9-like activities, Bax, Bcl2, CypD, ANT and cofilin expression. Mitochondrial dynamics (Mfn1, Mfn2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin and p62)-related proteins were measured by semi-quantitative Western blotting. DOX impaired behavioral performance, mitochondrial function, including lower resistance to mPTP and increased apoptotic signaling, decreased the content in OXPHOS complex subunits and increased oxidative stress in brain cortex and cerebellum. Molecular markers of mitochondrial biogenesis, dynamics and autophagy were also altered by DOX treatment in both brain subareas. Generally, TM and FW were able to mitigate DOX-related impairments in brain cortex and cerebellum mitochondrial activity, mPTP and apoptotic signaling. We conclude that the alterations in mitochondrial biogenesis, dynamics and autophagy markers induced by exercise performed before and during treatment may contribute to the observed protective brain cortex and cerebellum mitochondrial phenotype, which is more resistant to oxidative damage and apoptotic signaling in sub-chronically DOX treated animals.
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: I
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.
authors.forename: E
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: M M
authors.initials: MM
authors.lastname: Balça
authors.affiliation: CNC - Centre for Neuroscience and Cell Biology, University of Coimbra, Portugal; Institute of Physiology, Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: P I
authors.initials: PI
authors.lastname: Moreira
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Biocant Park, Cantanhede, Portugal.
authors.forename: P 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: J
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: A
authors.initials: A
authors.lastname: Ascensão
mesh_terms: D000818:Animals; D002525:Cerebellar Cortex / Q000378:metabolism* / Q000473:pathology; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010805:Physical Conditioning, Animal; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004317:Doxorubicin
keywords: Adriamycin; Apoptosis; Autophagy signaling; Brain bioenergetics; Exercise; Mitochondrial dynamics