title: Myocardial mitochondrial dysfunction in mice lacking adiponectin receptor 1.
abstract: Hypoadiponectinemia is an independent predictor of cardiovascular disease, impairs mitochondrial function in skeletal muscle, and has been linked to the pathogenesis of Type 2 diabetes. In models of Type 2 diabetes, myocardial mitochondrial function is impaired, which is improved by increasing serum adiponectin levels. We aimed to define the roles of adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) in adiponectin-evoked regulation of mitochondrial function in the heart. In isolated working hearts in mice lacking AdipoR1, myocardial oxygen consumption was increased without a concomitant increase in cardiac work, resulting in reduced cardiac efficiency. Activities of mitochondrial oxidative phosphorylation (OXPHOS) complexes were reduced, accompanied by reduced OXPHOS protein levels, phosphorylation of AMP-activated protein kinase, sirtuin 1 activity, and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling. Decreased ATP/O ratios suggested myocardial mitochondrial uncoupling in AdipoR1-deficient mice, which was normalized by lowering increased mitochondrial 4-hydroxynonenal levels following treatment with the mitochondria-targeted antioxidant Mn (III) tetrakis (4-benzoic acid) porphyrin. Lack of AdipoR2 did not impair mitochondrial function and coupling in the heart. Thus, lack of AdipoR1 impairs myocardial mitochondrial function and coupling, suggesting that impaired AdipoR1 signaling may contribute to mitochondrial dysfunction and mitochondrial uncoupling in Type 2 diabetic hearts.
authors.affiliation: Division of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Koentges
authors.forename: Alexandra
authors.initials: A
authors.lastname: König
authors.forename: Katharina
authors.initials: K
authors.lastname: Pfeil
authors.forename: Maximilian E
authors.initials: ME
authors.lastname: Hölscher
authors.forename: Tilman
authors.initials: T
authors.lastname: Schnick
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Andrea
authors.initials: A
authors.lastname: Schrepper
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cimolai
authors.forename: Sophia
authors.initials: S
authors.lastname: Kersting
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Judith
authors.initials: J
authors.lastname: Asal
authors.forename: Moritz
authors.initials: M
authors.lastname: Osterholt
authors.forename: Katja E
authors.initials: KE
authors.lastname: Odening
authors.forename: Torsten
authors.initials: T
authors.lastname: Doenst
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000502:physiology*; D009200:Myocardial Contraction; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000502:physiology*; D056564:Sirtuin 1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D054419:Receptors, Adiponectin; D014157:Transcription Factors; C475419:adiponectin receptor 1, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1