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Title: Cardiac energy metabolism in ischaemia and type 1 diabetes
Author: Lindsay, Ross
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Ischaemic heart disease represents a restriction of blood, and therefore oxygen, supply to the myocardium. This leads to a remodelling of cardiac metabolism, which can exacerbate production of damaging reactive oxygen species and tissue necrosis upon reperfusion. In a different paradigm of metabolic disease, the type-1 diabetic heart becomes more dependent upon the oxidation of fatty acids (FAO) for ATP synthesis due to an inability to regulate blood glucose concentration. The work presented in this thesis aimed to further our understanding of substrate selection and metabolism in the ischaemic and type-1 diabetic hearts. A mathematical network model for tracing universally-13C labelled metabolic substrates through the Krebs cycle using mass spectrometry was developed and presented. Experimentally-observed isotopologue distributions of Krebs cycle intermediates and proxies were interpreted using this model to determine the percentage of acetyl-CoA oxidised in the Krebs cycle which originated from the U-13C labelled substrate. In the Langendorff perfused rat heart, perfusion with intralipid resulted in greater functional recovery following ischaemia/reperfusion. Supplementation with dietary nitrate ablated this cardioprotective effect, but this highlights the importance of fatty acid oxidation to recovery from ischaemia/reperfusion injury. Ketogenesis was found to occur in the ischaemic heart, and was not specifically dependent upon either fatty acid or glucose oxidation. Its inhibition resulted in improved recovery of contractile function following ischaemia/reperfusion, suggesting the ketogenesis which occurs during cardiac ischaemia is a detrimental process. Isoprenaline administration conserved mitochondrial respiratory capacity and energetics in the type-1 diabetic rat heart. 10 weeks following removal of 90% of the pancreas (Px), mitochondrial respiratory capacity was impaired, with a substrate switch towards fatty acid oxidation (FAO) observed alongside greater expression of FAO-related enzymes and evidence of oxidative stress. Isoprenaline administration also impaired respiratory capacity, but enhanced flux through glycolysis. In the hearts of isoprenaline treated Px rats, mitochondrial respiratory capacity and energetics were conserved. In conclusion, cardiac ischaemia and type-1 diabetes both represent diseases where metabolic substrate oxidation is perturbed. FAO is not detrimental to the ischaemic or type-1 diabetic heart without associated loss of metabolic flexibility, and even appears beneficial to recovery following ischaemia/reperfusion.
Supervisor: Murray, Andrew J. ; Griffin, Julian L. Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Heart ; Metabolism ; Ischaemia ; Diabetes ; Mitochondria ; Langendorff ; 13C ; Metabolomics