Characterizing the Relationship Between Energy Metabolism and Mesenchymal Stem Cell Therapy in the Infarcted Heart
| atmire.migration.oldid | 1670 | |
| dc.contributor.advisor | Shearer, Jane | |
| dc.contributor.author | Hughey, Curtis | |
| dc.date.accessioned | 2013-12-13T22:33:25Z | |
| dc.date.available | 2014-03-15T07:00:16Z | |
| dc.date.issued | 2013-12-13 | |
| dc.date.submitted | 2013 | en |
| dc.description.abstract | Objective: A constant provision of adenosine triphosphate (ATP) is of necessity for cardiac contraction. If the heart progresses towards failure following a myocardial infarction (MI) it may undergo metabolic alterations that have the potential to compromise its ability to meet energetic demands. The main focus of this dissertation was to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in energy metabolism that contribute to ATP synthesis post-MI in the presence and absence of diet-induced insulin resistance. Methods: C57BL/6 mice were chow or high-fat fed prior to induction of a MI via chronic ligation of the left anterior descending coronary artery. Post-ligation, MSCs were transplanted via intramyocardial injection. Serial echocardiography was performed prior to and up to 28 days post-MI to evaluate cardiac systolic function. Hyperinsulinemic-euglycemic clamps coupled with the administration of isotopic tracers were employed post-MI to assess systemic insulin sensitivity and insulin-mediated, tissue-specific substrate uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponinpermeabilized cardiac fibers. Western blotting was completed to assist in identifying molecular mechanisms through which the MSC therapy may modulate cardiac and systemic metabolic phenotypes. Results: The improved systolic performance in MSC-treated mice was associated with a lessening of non-pathological in vivo insulin-stimulated cardiac glucose uptake. The changes in glucose uptake may have been via the MSC-mediated alterations in fatty acid availability/utilization. MSC therapy preserved fatty acid uptake in the absence of diet-induced insulin resistance. Conversely, the cell-based treatment reduced circulating nonesterified fatty acid concentration in high-fat fed mice. Additionally, potential impairments in insulin signalling may have been minimized as indicated by conservation of the p-Akt/Akt ratio. Down-stream of glucose uptake, the administration of MSCs conferred protective effects to mitochondrial oxidative phosphorylation efficiency, maximal function and mitochondrial content. Conclusions: The experiments conducted in this dissertation provide insight into the utility of MSC transplantation as a metabolic therapy for the metabolic perturbations that characterize insulin resistance in the infarcted heart. Also, these studies propose potential mechanisms of action that lead to an enhanced energetic and functional state in the infarcted heart following MSC transplantation. | en_US |
| dc.identifier.citation | Hughey, C. (2013). Characterizing the Relationship Between Energy Metabolism and Mesenchymal Stem Cell Therapy in the Infarcted Heart (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25306 | en_US |
| dc.identifier.doi | http://dx.doi.org/10.11575/PRISM/25306 | |
| dc.identifier.uri | http://hdl.handle.net/11023/1202 | |
| dc.language.iso | eng | |
| dc.publisher.faculty | Graduate Studies | |
| dc.publisher.institution | University of Calgary | en |
| dc.publisher.place | Calgary | en |
| dc.rights | University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. | |
| dc.subject | Physiology | |
| dc.subject.classification | myocardial infarction | en_US |
| dc.subject.classification | mesenchymal stem cell | en_US |
| dc.subject.classification | substrate uptake | en_US |
| dc.subject.classification | mitochondrial oxidative phosphorylation | en_US |
| dc.subject.classification | insulin clamp | en_US |
| dc.subject.classification | isotopic tracers | en_US |
| dc.title | Characterizing the Relationship Between Energy Metabolism and Mesenchymal Stem Cell Therapy in the Infarcted Heart | |
| dc.type | doctoral thesis | |
| thesis.degree.discipline | Biochemistry and Molecular Biology | |
| thesis.degree.grantor | University of Calgary | |
| thesis.degree.name | Doctor of Philosophy (PhD) | |
| ucalgary.item.requestcopy | true |