| Autor: |
Kerr M; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Miller JJ; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.; Oxford Centre for Clinical Magnetic Resonance Research, John Radcliffe Hospital, Oxford, United Kingdom.; Department of Physics, University of Oxford, Oxford, United Kingdom., Thapa D; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Stiewe S; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Timm KN; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Aparicio CNM; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Scott I; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Tyler DJ; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Heather LC; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. |
| Abstrakt: |
Cardiac energetic dysfunction has been reported in patients with type 2 diabetes (T2D) and is an independent predictor of mortality. Identification of the mechanisms driving mitochondrial dysfunction, and therapeutic strategies to rescue these modifications, will improve myocardial energetics in T2D. We demonstrate using 31P-magnetic resonance spectroscopy (31P-MRS) that decreased cardiac ATP and phosphocreatine (PCr) concentrations occurred before contractile dysfunction or a reduction in PCr/ATP ratio in T2D. Real-time mitochondrial ATP synthesis rates and state 3 respiration rates were similarly depressed in T2D, implicating dysfunctional mitochondrial energy production. Driving this energetic dysfunction in T2D was an increase in mitochondrial protein acetylation, and increased ex vivo acetylation was shown to proportionally decrease mitochondrial respiration rates. Treating T2D rats in vivo with the mitochondrial deacetylase SIRT3 activator honokiol reversed the hyperacetylation of mitochondrial proteins and restored mitochondrial respiration rates to control levels. Using 13C-hyperpolarized MRS, respiration with different substrates, and enzyme assays, we localized this improvement to increased glutamate dehydrogenase activity. Finally, honokiol treatment increased ATP and PCr concentrations and increased total ATP synthesis flux in the T2D heart. In conclusion, hyperacetylation drives energetic dysfunction in T2D, and reversing acetylation with the SIRT3 activator honokiol rescued myocardial and mitochondrial energetics in T2D. |
