Heart failure is a major cause of death in individuals with diabetes. Heart failure is characterized in part by mitochondrial dysfunction defined by decreased oxidative capacity and ATP synthesis. Diabetes is accompanied by a number of systemic changes including hyperlipidemia and hyperglycemia. A critical barrier in determining the molecular mechanisms that lead to the development of diabetes-related complications has been the availability of appropriate in vivo models to test each independently. To define the role of glucose delivery to the heart in the regulation of mitochondrial function we have developed a mouse model for inducible cardiomyocyte-specific expression of the glucose transporter, GLUT4. Thus allowing us to directly test the role that cardiomyocyte glucose delivery plays in the healthy and diseased heart. Our preliminary data define a model whereby increased glucose delivery in the basal state enhances glucose utilization. In stark contrast, increased glucose delivery in the presence of hyperglycemia accelerates the development of mitochondrial dysfunction. The long-term goal of my research is to determine the mechanisms controlling mitochondrial metabolic function in the heart. In this proposal, we will start by investigating the role of glucose-mediated mitochondrial regulation by examining glucose-delivery regulated post-translational modification of mitochondrial proteins (Aim 1) and epigenetic control of oxidative phosphorylation (OXPHOS) gene expression (Aim 2). The latter process has recently received significant attention for its contribution to "glycemic memory", defined as the impact that antecedent glucose concentrations have on persistently increasing the risk of diabetic complications independently of current levels of glycemic control.
For Specific Aim 1, we will determine the mitochondrial proteins that are modified by the post-translational modification O-linked GlcNAcylation, which is increased with diabetes, and begin to explore the functional consequences of glucose delivery on mitochondrial oxidative capacity and enzymatic function. Studies outlined in Aim 2, will define the role of epigenetic modifications associated with changes in OXPHOS gene expression that are uniquely regulated by glucose. The initial K99 phase of this proposal will facilitate training in aspects of proteomics (2D-PAGE and mass spectroscopy) and epigenetics (histone modifications and DNA methylation). This additional training will provide me with the knowledge and skill set to independently carry out my immediate short-term goal of finding a tenure-track position (R00 phase), necessary to complete the proposal's aims and pursue my interests in defining molecular mechanisms of cardiac dysfunction. Collectively, the completion of these studies will provide fundamental insights into the mechanistic basis for glucose in the development of diabetic cardiomyopathy and mitochondrial dysfunction.

Public Health Relevance

Heart failure is characterized by a decline in mitochondrial oxidative capacity and is a major cause of death in individuals with diabetes. We have developed a novel mouse model for inducible cardiac specific overexpression of the glucose transporter 4 (GLUT4). These studies will determine the contribution of cellular glucose uptake in the development of mitochondrial dysfunction in the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
4R00HL111322-03
Application #
8672908
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wong, Renee P
Project Start
2013-08-02
Project End
2016-07-31
Budget Start
2013-08-02
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$237,047
Indirect Cost
$75,699
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Lopez-Izquierdo, Angelica; Pereira, Renata O; Wende, Adam R et al. (2014) The absence of insulin signaling in the heart induces changes in potassium channel expression and ventricular repolarization. Am J Physiol Heart Circ Physiol 306:H747-54