Votion 2018 MiP2018

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Dominique-Marie Votion
Functional diagnosis of mitochondrial defects in equine atypical myopathy and targeted mitochondrial therapy: a preliminary study.

Link: MiP2018

Zhou Y, Gonzalez-Medina S, Gustin P, Mouithys-Mickalad A, Piercy RJ, Marcillaud-Pitel C, Lemieux H, Votion DM (2018)

Event: MiP2018

COST Action MitoEAGLE

Equine atypical myopathy (AM) is an acute environmental intoxication resulting from hypoglycin A (HGA) ingestion. In Europe, seeds and seedlings of Acer pseudoplatanus (sycamore maple tree) are the primarily sources of this naturally-occurring toxin [1]. Out of Europe, ackee and lychee may also cause HGA poisoning in human [2,3]. Metabolism of ingested HGA produces methylenecyclopropylacetic acid (MCPA) which impairs fatty acid metabolism with subsequent increased use of glucose. As a consequence, human and laboratory animals suffer from an acute hypoglycaemic syndrome due to blockade of gluconeogenesis after depletion of hepatic glycogen stores. In contrast, intoxicated equids usually show hyperglycaemia and suffer from a severe rhabdomyolysis syndrome targeting muscle groups enriched in mitochondria, such as postural, respiratory, and cardiac muscles [4]. Although HGA poisoning has been extensively studied in regard to the inhibition of mitochondrial β-oxidation and the mechanism leading to hypoglycaemia, the impact on mitochondrial respiration has been overlooked. In a previous study, a severe decrease (up to 49%) in mitochondrial respiration was observed in muscle microbiopsies taken from horses suffering from AM with NADH-linked substrates and succinate used separately (N, S) or in cocktail (NS) to stimulate respiration [5]. Thus, mitochondrial toxicity of HGA and/ or MCPA is not solely associated to fatty acid metabolism disturbance.

To better understand the functional mitochondrial defects associated with AM and identify potential treatments, an in vitro model is needed. Firstly, we have observed that addition of serum of AM-affected horses (which contains HGA, MCPA and a general increase in acylcarnitine species) on cultured equine myoblasts depresses NS-linked respiration. Secondly, we have showed that MCPA but not HGA decreases OXPHOS capacity of N, S and NS-pathways in a dose-dependent manner. Thirdly, we have included short, medium and long chain fatty acids as substrates and confirmed inhibition of fatty acid (F) pathway by MCPA but not HGA.

Although these protocols do not reveal the MCPA action site(s), these respirometric studies may serve as a basis for evaluating the effectiveness of selected therapeutics assumed to be of value to prevent and/ or counteract the mitochondrial dysfunction associated to HGA poisoning.


Bioblast editor: Plangger M, Kandolf G O2k-Network Lab: BE Liege Votion DM, CA Edmonton Lemieux H


Labels: MiParea: Respiration, Pharmacology;toxicology 


Organism: Horse  Tissue;cell: Skeletal muscle  Preparation: Intact cells 


Coupling state: OXPHOS  Pathway: F, N, S, NS  HRR: Oxygraph-2k 


Affiliations

Zhou Y(1,2), Gonzalez-Medina S(3), Gustin P(2), Mouithys-Mickalad A(4), Piercy RJ(3), Marcillaud-Pitel C(5), Lemieux H(6), Votion DM(7)

  1. Fac Medicine, Shanghai Jiao Tong Univ, China
  2. Dept Functional Sciences, Fundamental Applied Research Animals Health (FARAH), Fac Veterinary Medicine, Univ Liege, Belgium
  3. Comparative Neuromuscular Diseases Lab, The Royal Veterinary College, London, UK
  4. Centre l’Oxygène, Recherche Développement (CORD), FARAH, Univ Liege, Belgium
  5. Réseau d’EpidémioSurveillance Pathologie Equine (RESPE), Caen, France
  6. Fac Saint-Jean, Univ Alberta, Edmonton, AB, Canada
  7. Equine Pole, FARAH, Fac Veterinary Medicine, Univ Liege, Belgium. - dominique.votion@Uliege.be


References and Support

  1. Baise E, Habyarimana JA, Amory H, Boemer F, Douny C, Gustin P, Marcillaud-Pitel C, Patarin F, Weber M, Votion DM (2016) Samaras and seedlings of Acer pseudoplatanus are potential sources of hypoglycin A intoxication in atypical myopathy without necessarily inducing clinical signs. Equine Vet J 48:414-7.
  2. Barceloux DG (2009) Akee fruit and Jamaican vomiting sickness (Blighia sapida Koenig). Dis Mon 55:318-26.
  3. Shrivastava A, Kumar A, Thomas JD, Laserson KF, Bhushan G, Carter MD, Chhabra M, Mittal V, Khare S, Sejvar JJ, Dwivedi M, Isenberg SL, Johnson R, Pirkle JL, Sharer JD, Hall PL, Yadav R, Velayudhan A, Papanna M, Singh P, Somashekar D, Pradhan A, Goel K, Pandey R, Kumar M, Kumar S, Chakrabarti A, Sivaperumal P, Kumar AR, Schier JG, Chang A, Graham L A, Mathews TP, Johnson D, Valentin L, Caldwell KL, Jarrett JM, Harden LA, Takeoka GR, Tong S, Queen K, Paden C, Whitney A, Haberling DL, Singh R, Singh RS, Earhart KC, Dhariwal AC, Chauhan LS, Venkatesh S, Srikantiah P (2017) Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study. Lancet Glob Health 5:e458-e66.
  4. Votion DM (2016) Atypical myopathy: an update. In Practice 38:241-6.
  5. Lemieux H, Boemer F, van Galen G, Serteyn D, Amory H, Baise E, Cassart D, van Loon G, Marcillaud-Pitel C, Votion DM (2016) Mitochondrial function is altered in horse atypical myopathy. Mitochondrion 30:35-41.

These studies were supported by grants from the “Fonds Spéciaux pour la Recherche (FSR)” of Liège University of Belgium, the “Institut français du cheval et de l'équitation (Ifce)” of France and “The Horse Trust (G6015)” of United Kingdom.