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Exercise mitigates diclofenac‐induced liver mitochondrial dysfunction
Author(s) -
SantosAlves Estela,
MarquesAleixo Ines,
Coxito Pedro,
Balça Maria M.,
RizoRoca David,
RochaRodrigues Silvia,
Martins Sandra,
Torrella Joan R.,
Oliveira Paulo J.,
Moreno Antonio J.,
Magalhães José,
Ascensão António
Publication year - 2014
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/eci.12285
Subject(s) - mptp , oxidative stress , mitochondrial permeability transition pore , sirt3 , aconitase , mitochondrion , pharmacology , diclofenac , oxidative phosphorylation , chemistry , apoptosis , endocrinology , biology , medicine , biochemistry , programmed cell death , nad+ kinase , dopaminergic , dopamine , sirtuin , enzyme
Background Several strategies have been developed to counteract liver injury as a consequence of nonsteroid anti‐inflammatory drugs toxicity. Here, we aimed to determine whether physical exercise results in liver mitochondrial protection against in vitro diclofenac toxicity. Material and methods Male adult Sprague‐Dawley rats were divided into sedentary, 12‐week endurance training ( ET ) and voluntary activity ( VPA ). In vitro liver mitochondrial function as assessed by oxygen consumption, transmembrane electric potential (ΔΨ) and susceptibility to the mitochondrial permeability transition pore ( MPTP ) was evaluated in the absence and presence of diclofenac. Mitochondrial oxidative stress markers [Mn SOD , aconitase, ‐ SH and MDA , SIRT 3, p66shc(Ser36)/p66shc ratio] and apoptotic signalling (caspases 3, 8 and 9, Bax, Bcl‐2 and CypD) were assessed. Content of OXPHOS components and qualitative liver morphological evaluation were assessed. Results Despite no effects of ET and VPA on basal liver mitochondrial oxygen consumption or ΔΨ endpoints, exercised animals showed lower susceptibility to MPTP . Diclofenac‐induced decrease in ΔΨ, increased state 4 respiration and susceptibility to MPTP opening were all prevented by exercise. Under untreated conditions, VPA group showed higher aconitase activity, while ET decreased MDA and increased Bax content. VPA decreased p66shc(Ser36), complex III and V OXPHOS subunits. Both ET and VPA increased complex IV OXPHOS subunit, and SIRT 3 and Bcl‐2 content and decreased caspase 9 activity. Unexpectedly, ET and VPA decreased ANT . Conclusions Both chronic physical exercise models augmented the resistance to in vitro diclofenac‐induced mitochondrial alterations, including increased MPTP susceptibility, possibly by modulating oxidative stress and MPTP regulators.