title: Cobalamin and folate protect mitochondrial and contractile functions in a murine model of cardiac pressure overload.
abstract: PGC-1α, a key regulator of energy metabolism, seems to be a relevant therapeutic target to rectify the energy deficit observed in heart failure (HF). Since our previous work has shown positive effects of cobalamin (Cb) on PGC-1α cascade, we investigate the protective role of Cb in pressure overload-induced myocardial dysfunction. Mice were fed with normal diet (ND) or with Cb and folate supplemented diet (SD) 3weeks before and 4weeks after transverse aortic constriction (TAC). At the end, left ventricle hypertrophy and drop of ejection fraction were significantly lower in SD mice than in ND mice. Alterations in mitochondrial oxidative capacity, fatty acid oxidation and mitochondrial biogenesis transcription cascade were markedly improved by SD. In SD-TAC mice, lower expression level of the acetyltransferase GCN5 and upregulation of the methyltransferase PRMT1 were associated with a lower protein acetylation and a higher protein methylation levels. This was accompanied by a sustained expression of genes involved in mitochondrial biogenesis transcription cascade (Tfam, Nrf2, Cox1 and Cox4) after TAC in SD mice, suggesting a preserved activation of PGC-1α; this could be at least partly due to corrected acetylation/methylation status of this co-activator. The beneficial effect of the treatment would not be due to an effect of Cb and folate on oxidative stress or on homocysteinemia, which were unchanged by SD. These results showed that Cb and folate could protect the failing heart by preserving energy status through maintenance of mitochondrial biogenesis. It reinforces the concept of a metabolic therapy of HF.
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France. Electronic address: jerome.piquereau@u-psud.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Piquereau
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Moulin
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Giada
authors.initials: G
authors.lastname: Zurlo
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gressette
authors.affiliation: Service de Biochimie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Paul
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemaire
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Veksler
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Châtenay-Malabry, France; UMR-S 1180, Inserm, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
mesh_terms: D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005492:Folic Acid / Q000494:pharmacology*; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D020138:Hyperhomocysteinemia / Q000378:metabolism; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D014805:Vitamin B 12 / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D005492:Folic Acid; D014805:Vitamin B 12
keywords: B vitamins; Cellular energetics; Metabolic therapy; Mitochondrial function; Myocardial dysfunction