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Exercise and Doxorubicin Treatment Modulate Cardiac Mitochondrial Quality Control Signaling

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Abstract

The cross-tolerance effect of exercise against heart mitochondrial-mediated quality control, remodeling and death-related mechanisms associated with sub-chronic Doxorubicin (DOX) treatment is yet unknown. We therefore analyzed the effects of two distinct chronic exercise models (endurance treadmill training—TM and voluntary free wheel activity—FW) performed during the course of the sub-chronic DOX treatment on mitochondrial susceptibility to permeability transition pore (mPTP), apoptotic and autophagic signaling and mitochondrial dynamics. Male Sprague–Dawley rats were divided into six groups (n = 6 per group): saline sedentary (SAL + SED), SAL + TM (12-weeks treadmill), SAL + FW (12-weeks voluntary free-wheel), DOX + SED [7-weeks sub-chronic DOX treatment (2 mg kg−1 week−1)], DOX + TM and DOX + FW. Apoptotic signaling and mPTP regulation were followed by measuring caspase 3, 8 and 9 activities, Bax, Bcl2, CypD, ANT, and cophilin expression. Mitochondrial dynamics (Mfn1, Mfn2, OPA1 and DRP1) and auto(mito)phagy (LC3, Beclin1, Pink1, Parkin and p62)-related proteins were semi-quantified. DOX treatment results in augmented mPTP susceptibility and apoptotic signaling (caspases 3, 8 and 9 and Bax/Bcl2 ratio). Moreover, DOX decreased the expression of fusion-related proteins (Mfn1, Mfn2, OPA1), increased DRP1 and the activation of auto(mito)phagy signaling. TM and FW prevented DOX-increased mPTP susceptibility and apoptotic signaling, alterations in mitochondrial dynamics and inhibits DOX-induced increases in auto(mito)phagy signaling. Collectively, our results suggest that both used chronic exercise models performed before and during the course of sub-chronic DOX treatment limit cardiac mitochondrial-driven apoptotic signaling and regulate alterations in mitochondrial dynamics and auto(mito)phagy in DOX-treated animals.

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Acknowledgements

This study was supported by Portuguese Foundation of Science and Technology (FCT) grants (SFRH/BD/61889/2009 and SFRH/BPD/108322/2015 to IMA, SFRH/BD/112983/2015 to ESA, PTDC/DTP-DES/1071/2012 to AA, P2020-PTDC/DTP-DES/7087/2014 to JM, PTDC/SAU-TOX/117912/2010 to PO, Pest-C/SAU/LA0001/2013-2014 to CNC and UID/DTP/00617/2013 to CIAFEL). The authors acknowledge the collaboration of Dr. Maria Manuel Balça, Dr. Diogo Mariani and Dr. André Ferreira for their technical assistance regarding animals’ care and training protocols and to Dr. Claudia Deus, Dr. Maria José Mendes and Dr. Lucília Penteado for their support.

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  1. CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Rua Dr. Plácido Costa 91, 4200-450, Porto, Portugal

    I. Marques-Aleixo, E. Santos-Alves, J. Magalhães & A. Ascensão

  2. Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain

    E. Santos-Alves & J. R. Torrella

  3. CNC - Centre for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    P. J. Oliveira

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  1. I. Marques-Aleixo
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Marques-Aleixo, I., Santos-Alves, E., Torrella, J.R. et al. Exercise and Doxorubicin Treatment Modulate Cardiac Mitochondrial Quality Control Signaling. Cardiovasc Toxicol 18, 43–55 (2018). https://doi.org/10.1007/s12012-017-9412-4

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  • DOI: https://doi.org/10.1007/s12012-017-9412-4

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