Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore in doxorubicin treated rats

António A Ascensão (1) , José Lumini-Oliveira , Nuno G Machado , Rita M Ferreira , Inês O Gonçalves , Ana C Moreira , Franklin Marques , Vilma A Sardão , Paulo J Oliveira , José Magalhães

1 Sports Biology

Doxorubicin (DOX), an antibiotic used in oncologic treatments, is limited by a dose-related cardiotoxicity, against which acute exercise is protective. However, the mechanisms related to this protection involving mitochondria remain unknown. Therefore, we aimed to determine the effects of an acute endurance exercise bout performed 24h before Doxorubicin (DOX) treatment on heart and liver mitochondrial function. Twenty adult Wistar-male rats were divided as follows: non-exercised saline (NE+SAL), non-exercised DOX (NE+DOX), exercised-saline (EX+SAL) and exercised-DOX (EX+DOX). The animals performed a 60 min exercise bout on a treadmill or remained sedentary 24h before receiving either a 20 mg.kg-1 DOX bolus or saline. Heart and liver mitochondrial function (oxygen consumption, membrane potential (ΔΨ) and cyclosporin-A-sensitive calcium-induced mitochondrial permeability transition pore (MPTP) opening) were evaluated. Respiratory complex, MnSOD, caspase 3 and 9 activities as well as ANT, VDAC, Cyclophylin D, Bax and Bcl-2 contents were also measured. Acute exercise prevented the decreased cardiac mitochondrial function (state 3, phosphorylative lagphase, maximal ΔΨ generated both with complex I and II-linked substrates and calcium-induced MPTP opening) induced by DOX treatment. Exercise also prevented DOX-induced decreased 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 mitochondrial permeability transition pore and apoptosis-related proteins determined in heart and liver mitochondria. Data demonstrate that acute exercise protects against cardiac mitochondrial dysfunction, preserving mitochondrial phosphorylation capacity and attenuating DOX-induced decreased tolerance to MPTP opening.

Mots clés: Medicine

António A Ascensão, José Lumini-Oliveira, Nuno G Machado, Rita M Ferreira, Inês O Gonçalves, et al.. Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore in doxorubicin treated rats. Clinical Science, 2010, 120 (1), pp.37-49. ⟨10.1042/CS20100254⟩. ⟨hal-00624425⟩