4.3 Article

Exercise and Doxorubicin Treatment Modulate Cardiac Mitochondrial Quality Control Signaling

期刊

CARDIOVASCULAR TOXICOLOGY
卷 18, 期 1, 页码 43-55

出版社

HUMANA PRESS INC
DOI: 10.1007/s12012-017-9412-4

关键词

Chronic exercise; Adriamycin; Heart mitochondria; Cardiac cell death; Mitochondrial quality control

资金

  1. Portuguese Foundation of Science and Technology (FCT) [SFRH/BD/61889/ 2009, SFRH/BPD/108322/2015, SFRH/BD/112983/2015, PTDC/DTP-DES/1071/2012, P2020-PTDC/DTP-DES/7087/2014, PTDC/SAU-TOX/117912/2010, Pest-C/SAU/LA0001/2013-2014, UID/DTP/00617/2013]
  2. Fundação para a Ciência e a Tecnologia [SFRH/BD/112983/2015, SFRH/BPD/108322/2015, SFRH/BD/61889/2009, PTDC/DTP-DES/1071/2012, PTDC/SAU-TOX/117912/2010] Funding Source: FCT

向作者/读者索取更多资源

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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