title: Endurance training prevents negative effects of the hypoxia mimetic dimethyloxalylglycine on cardiac and skeletal muscle function.
abstract: Hypoxic preconditioning is a promising strategy to prevent hypoxia-induced damages to several tissues. This effect is related to prior stabilization of the hypoxia-inducible factor-1α via inhibition of the prolyl-hydroxylases (PHDs), which are responsible for its degradation under normoxia. Although PHD inhibition has been shown to increase endurance performance in rodents, potential side effects of such a therapy have not been explored. Here, we investigated the effects of 1 wk of dimethyloxalylglycine (DMOG) treatment (150 mg/kg) on exercise capacity, as well as on cardiac and skeletal muscle function in sedentary and endurance-trained rats. DMOG improved maximal aerobic velocity and endurance in both sedentary and trained rats. This effect was associated with an increase in red blood cells without significant alteration of skeletal muscle contractile properties. In sedentary rats, DMOG treatment resulted in enhanced left ventricle (LV) weight together with impairment in diastolic function, LV relaxation, and pulse pressure. Moreover, DMOG decreased maximal oxygen uptake (state 3) of isolated mitochondria from skeletal muscle. Importantly, endurance training reversed the negative effects of DMOG treatment on cardiac function and restored maximal mitochondrial oxygen uptake to the level of sedentary placebo-treated rats. In conclusion, we provide here evidence that the PHD inhibitor DMOG has detrimental influence on myocardial and mitochondrial function in healthy rats. However, one may suppose that the deleterious influence of PHD inhibition would be potentiated in patients with already poor physical condition. Therefore, the present results prompt us to take into consideration the potential side effects of PHD inhibitors when administrated to patients.
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France; Université de Montpellier, Montpellier, France; ffavier@univ-montp1.fr.
authors.forename: Francois B
authors.initials: FB
authors.lastname: Favier
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France; Université de Montpellier, Montpellier, France;
authors.forename: Florian A
authors.initials: FA
authors.lastname: Britto
authors.affiliation: Laboratoire de Pharm-écologie cardiovasculaire, Avignon, France; and Université d'Avignon, Avignon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ponçon
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France; Université de Montpellier, Montpellier, France;
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Begue
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France; Université de Montpellier, Montpellier, France;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Chabi
authors.affiliation: Laboratoire de Pharm-écologie cardiovasculaire, Avignon, France; and Université d'Avignon, Avignon, France.
authors.forename: Cyril
authors.identifier: http://orcid.org/0000-0001-5181-3827
authors.initials: C
authors.lastname: Reboul
authors.affiliation: Laboratoire de Pharm-écologie cardiovasculaire, Avignon, France; and Université d'Avignon, Avignon, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Meyer
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France; Université de Montpellier, Montpellier, France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Py
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000378:metabolism*; D000818:Animals; D006321:Heart / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D009135:Muscular Diseases / Q000378:metabolism / Q000503:physiopathology; D009142:Musculoskeletal Physiological Phenomena; D009206:Myocardium / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000600:Amino Acids, Dicarboxylic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C040947:oxalylglycine
keywords: 2-oxoglutarate; exercise; heart; mitochondrial respiration; prolyl hydroxylase inhibitor