Characterized by excessive myocardial glycogen deposition, cardiac hypertrophy, frequent cardiac arrhythmias and progressive conduction system disease, the PRKAG2 cardiac syndrome stems from a genetic mutation in the γ2-subunit of AMP-activated protein kinase (AMPK). Although functionally diverse, the main role of AMPK is to modulate cardiac metabolism in response to depleted ATP levels. A comprehensive study of the dysfunctional regulation of AMPK activity involved in the progression of the human PRKAG2 cardiac syndrome is hindered by the limitations of in vitro techniques. Positron emission tomography (PET) imaging with the glucose analogue, FDG, offers a quantitative assessment of myocardial glucose uptake non-invasively. The aim of this thesis was to determine the ability of FDG to detect changes in glucose uptake, storage and metabolism in the heart in relation to AMPK activity and provide insights into the mechanism of PRKAG2 cardiac hypertrophy. To achieve this aim, a transgenic AMPK γ2-subunit Arg302Gln mouse model was evaluated with small animal FDG PET with correlation to biochemical assays of cardiac AMPK activity and the glycogen metabolism pathway. Using the vena cava blood input function, FDG myocardial glucose uptake was reliably assessed in mice for the first time with Patlak modeling. Reduced FDG uptake in the Arg302Gln PRKAG2 mouse model suggested a feedback pathway reducing exogenous glucose uptake due to excessive intracellular glycogen stores. Despite an increase in FDG uptake in the skeletal muscle of the PRKAG2 mutant mice following insulin stimulation, there was no change in cardiac uptake, signifying myocardial insulin resistance. Increased reliance on glucose oxidation by TMZ inhibition of fatty acid oxidation reduced glycogen stores, restored cardiac function and eliminated ventricular preexcitation. The observed reduction in mouse myocardial FDG uptake mirrors the reduction previously observed in the human PRKAG2 patients. The potential now exists to evaluate both progression and therapeutic interventions for the PRKAG2 cardiac syndrome with the transgenic mouse model with translation to the affected patients using FDG cardiac imaging.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU.#10393/24045 |
| Date | 23 April 2013 |
| Creators | Thorn, Stephanie |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thèse / Thesis |
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