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: Christoph Koentges, Alexandra König, Katharina Pfeil, Maximilian E Hölscher, Tilman Schnick, Adam R Wende, Andrea Schrepper, Maria C Cimolai, Sophia Kersting, Michael M Hoffmann, Judith Asal, Moritz Osterholt, Katja E Odening, Torsten Doenst, Lutz Hein, E Dale Abel, Christoph Bode, Heiko Bugger
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 110 Issue 4 Pg. 37 ( 2015) ISSN: 1435-1803 [Electronic] Germany
• PMID: 25982881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Reactive Oxygen Species
• Receptors, Adiponectin
• Transcription Factors
• adiponectin receptor 1, mouse
• AMP-Activated Protein Kinases
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• AMP-Activated Protein Kinases (physiology)
• Animals
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria, Heart (physiology)
• Myocardial Contraction
• Oxidative Phosphorylation
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Reactive Oxygen Species (metabolism)
• Receptors, Adiponectin (physiology)
• Sirtuin 1 (physiology)
• Transcription Factors (physiology)