AKT and mTOR in the Heart

Update item information
Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Zhu, Yi
Title AKT and mTOR in the Heart
Date 2012-12
Description Insulin resistance is an independent risk factor for heart disease. In cardiac muscle, PI3K-Akt signaling is persistently activated, despite a reduction in glucose uptake. Given that persistent activation of PI3K and Akt in the heart may be a consequence of hyperinsulinemia in insulin resistant states, the study in Chapter 2 was designed to determine if constitutive activation of PI3K and Akt signaling in the heart could independently impair insulin-mediated glucose uptake and GLUT4 translocation. The study was initially predicated on the hypothesis that chronic activation of PI3K and Akt signaling would activate mTORC1-mediated S6K-IRS negative feedback signaling and desensitize insulin-mediated glucose transport. Unexpectedly, the study discovered that PI3K and Akt activation impairs myocardial glucose uptake prior to any evidence of S6K activation despite normal translocation of GLUT4 in cardiomyocytes. These data indicate that activation of PI3K and Akt may impair glucose uptake via mechanisms that impair the intrinsic activity of the GLUT4 transporter. Insulin signaling and many other cellular signaling pathways converge at mTOR, which has been intensively studied in cell culture and different mouse tissues. However, the role of mTOR in cardiac development has never been studied. In Chapter 3, an inducible mTOR deficient mouse model was generated for studying the role of mTOR in cardiac bioenergetics. A decrease of fatty acid utilization, which leads to an impairment in ATP production, was identified in the mTOR deficient heart prior to development of cardiac dysfunction and lethality of the mice. Ongoing studies are focusing on the mechanisms of how mTOR regulates fatty acid metabolism in the heart. Taken together, this dissertation has advanced our understanding of insulin signaling in regulation of glucose uptake and GLUT4 translocation in the heart, as well as the role of mTOR in cardiac development and cardiac bioenergetics.
Type Text
Publisher University of Utah
Subject MESH Insulin Resistance; Heart Diseases; Energy Metabolism; Regulatory-Associated Protein of mTOR; Diabetes Mellitus; Insulin Receptor Substrate Proteins; Protein Kinases; Signal Transduction; Glucose; Glucose Transporter Type 4; Heart Failure; TOR Serine-Threonine Kinases; Adenosine Triphosphate; Phosphorylation
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of AKT and mTOR in the Heart
Rights Management Copyright © Yi Zhu 2012
Format Medium application/pdf
Format Extent 1,497,263 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6rv5199
Setname ir_etd
Date Created 2019-02-14
Date Modified 2021-05-06
ID 1400324
Reference URL https://collections.lib.utah.edu/ark:/87278/s6rv5199