Glucose Oxidation Control in the Heart

• Author / Creator

  Fillmore, Natasha

• Heart failure is associated with major changes in cardiac energy metabolism that decrease cardiac efficiency, which can reduce cardiac function. In severe heart failure there is a shift back toward a fetal heart metabolism, with a decrease in mitochondrial oxidative metabolism and increase in glycolysis, which decreases efficiency. This increased reliance on glycolysis may also contribute to hypertrophy in failing hearts. In response to these observations I became interested in better understanding the changes in energy metabolism that occur on both sides of this continuum of cardiac myocyte maturity and cell growth: cardiac myocyte differentiation and the development of heart failure. Because insulin resistance is believed to decrease cardiac efficiency and is an important contributing factor in the development of heart failure, I also examined the regulation of energy metabolism in cardiac insulin resistance and whether improving cardiac efficiency could improve cardiac function in insulin resistant hearts. We first focused on the changes in energy metabolism that occur during cardiac myocyte differentiation. To get a better understanding of stem cell energy metabolism I initially characterized energy metabolism of bone marrow mesenchymal stem cells (BMMSC). I showed that BMMSCs derive >97% of ATP production from glycolysis, with the rest coming from glucose and fatty acid oxidation. In the course of these experiments I also discovered that physiological levels of the saturated fatty acid palmitate decrease BMMSC proliferation and cell survival. Interestingly, the unsaturated fatty acid oleate both protects against detrimental effects of palmitate as well as the decline in palmitate oxidation induced by palmitate treatment. Energy metabolism was then measured in H9C2 cells differentiated toward cardiac myocytes for 7 days. I found that there was a significant increase in glucose oxidation but no significant changes in glycolysis or palmitate oxidation in the differentiated H9C2 cells. Insulin resistance results in changes in cardiac energy metabolism which are believed to contribute to the development of heart failure. I, therefore, focused on the importance of this decline in glucose oxidation in insulin resistant hearts on the development of cardiac dysfunction. To do this, db/db mice were treated for 4 wk with either vehicle or insulin glargine and analysis of in vivo cardiac function via echocardiography revealed an improvement in cardiac function. Based on ex vivo metabolic and cardiac function measurements using the isolated working heart perfusion I speculate that acute stimulation of glucose oxidation by insulin glargine contributes to the improved cardiac function observed. We then assessed the changes in cardiac energy metabolism that occur during development of heart failure with preserved ejection fraction (HFpEF). Changes in cardiac energy metabolism were assessed in Dahl salt-sensitive rats fed a high salt diet (HSD), which induces HFpEF, for 0, 3, 6 or 9 wk. Over the course of 9 wk, the HSD increased glycolysis but did not alter glucose oxidation resulting in increased uncoupling of glycolysis and glucose oxidation. After 9 wk the HSD also decreased palmitate oxidation. These results show that the coupling of glycolysis and glucose oxidation is reduced during the development of HFpEF. Because of the link between heart failure and insulin resistance I also wanted to better understanding the mechanisms involved in the decreased ability of insulin to stimulate glucose oxidation in insulin resistant hearts. A better understanding of the regulation of cardiac insulin resistance could provide clues to the mechanisms involved in the development of heart failure. We chose to focus on branched chain amino acid oxidation because BCAAs have both been implicated in insulin resistance and there is some indirect evidence to indicate that BCAAs could be involved in heart failure. We tested the proposal that an elevation in BCAA oxidation induces insulin resistance by competing with flux through glucose oxidation and fatty acid oxidation. Our results showed that BCAA oxidation contributes a small amount of the overall ATP production in the heart and is further reduced in response to high fat diet induced insulin resistance. These results suggest that cardiac insulin resistance is not due to BCAA oxidation inhibition of glucose and fatty acid oxidation. Overall, the results presented in this thesis suggest that stimulating glucose oxidation may be a promising strategy to improve cardiac myocyte differentiation, improve the function of insulin resistant hearts, and treat heart failure.

• Subjects / Keywords

  • Glucose oxidation
  • Heart failure
  • Insulin resistance
  • Energy metabolism
  • Fatty acids
  • Cardiac myocyte differentiation
  • Bone marrow mesenchymal stem cell

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3Q23R511

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.