title: Metabolomic profiling of the heart during acute ischemic preconditioning reveals a role for SIRT1 in rapid cardioprotective metabolic adaptation.
abstract: Ischemic preconditioning (IPC) protects tissues such as the heart from prolonged ischemia-reperfusion (IR) injury. We previously showed that the lysine deacetylase SIRT1 is required for acute IPC, and has numerous metabolic targets. While it is known that metabolism is altered during IPC, the underlying metabolic regulatory mechanisms are unknown, including the relative importance of SIRT1. Thus, we sought to test the hypothesis that some of the metabolic adaptations that occur in IPC may require SIRT1 as a regulatory mediator. Using both ex-vivo-perfused and in-vivo mouse hearts, LC-MS/MS based metabolomics and (13)C-labeled substrate tracing, we found that acute IPC altered several metabolic pathways including: (i) stimulation of glycolysis, (ii) increased synthesis of glycogen and several amino acids, (iii) increased reduced glutathione levels, (iv) elevation in the oncometabolite 2-hydroxyglutarate, and (v) inhibition of fatty-acid dependent respiration. The majority (83%) of metabolic alterations induced by IPC were ablated when SIRT1 was acutely inhibited with splitomicin, and a principal component analysis revealed that metabolic changes in response to IPC were fundamentally different in nature when SIRT1 was inhibited. Furthermore, the protective benefit of IPC was abrogated by eliminating glucose from perfusion media while sustaining normal cardiac function by burning fat, thus indicating that glucose dependency is required for acute IPC. Together, these data suggest that SIRT1 signaling is required for rapid cardioprotective metabolic adaptation in acute IPC.
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: William
authors.initials: W
authors.lastname: Urciuoli
authors.affiliation: Department of Pharmacology & Physiology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Xenia
authors.initials: X
authors.lastname: Schafer
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Munger
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: paul_brookes@urmc.rochester.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
mesh_terms: D000222:Adaptation, Physiological; D000596:Amino Acids / Q000096:biosynthesis; D000818:Animals; D019069:Cell Respiration; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D005977:Glutarates / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D006003:Glycogen / Q000096:biosynthesis; D006019:Glycolysis / Q000235:genetics; D019157:Ischemic Preconditioning, Myocardial; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology; D009924:Organ Culture Techniques; D025341:Principal Component Analysis; D011753:Pyrones / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D005977:Glutarates; D009281:Naphthalenes; D011753:Pyrones; C019417:alpha-hydroxyglutarate; C444426:splitomicin; D006003:Glycogen; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005978:Glutathione
keywords: Fatty acids; Glucose; Ischemia; Preconditioning; Reperfusion; Sirtuin