title: Exercise mitigates diclofenac-induced liver mitochondrial dysfunction.
abstract: 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.
  
  
  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 [MnSOD, aconitase, -SH and MDA, SIRT3, 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 SIRT3 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.
authors.affiliation: CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal.
authors.forename: Estela
authors.initials: E
authors.lastname: Santos-Alves
authors.forename: Ines
authors.initials: I
authors.lastname: Marques-Aleixo
authors.forename: Pedro
authors.initials: P
authors.lastname: Coxito
authors.forename: Maria M
authors.initials: MM
authors.lastname: Balça
authors.forename: David
authors.initials: D
authors.lastname: Rizo-Roca
authors.forename: Silvia
authors.initials: S
authors.lastname: Rocha-Rodrigues
authors.forename: Sandra
authors.initials: S
authors.lastname: Martins
authors.forename: Joan R
authors.initials: JR
authors.lastname: Torrella
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Moreno
authors.forename: José
authors.initials: J
authors.lastname: Magalhães
authors.forename: António
authors.initials: A
authors.lastname: Ascensão
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D004008:Diclofenac / Q000633:toxicity*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D012119:Respiration
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D009498:Neurotoxins; D004008:Diclofenac; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Apoptotic signalling; bioenergetics; exercise; liver toxicity; nonsteroid anti-inflammatory drugs; oxidative stress