Heart failure is characterized by the inability of the heart to meet the demands of the body, often through inadequate ventricular filling or pumping. Progression into this compromised state is marked by several structural and biochemical changes to the myocardium. A modification germane to the study at hand is the altered energetic and metabolic status of the cardiomyocyte. Therefore, the purpose of this study is to understand how regulators of energetic status, liver kinase B 1 (LKB1) and AMP-activated protein kinase (AMPK), interact with and alter function of the greatest energy consumer in the heart, the myofilament. Using measures of muscle myofilament function and post-translational modification status, relative activation of the LKB1/AMPK pathway was found to differentially alter contractility, cross-bridge kinetics, Myosin Binding Protein C phosphorylation, and Troponin I phosphospecies distribution. LKB1 complex treatment of cardiac trabeculae was shown to blunt contractility and maximum tension generation. Furthermore, regulation of the LKB1 complex was examined. The LKB1 complex was shown to alter its association with myofibrillar proteins, depending on the energetic state of the cardiomyocyte. The LKB1 complex was found localize in the region of the Z-Disk of the cardiac sarcomere, and potentially associate with both mitochondrial and mechanotransduction regulatory proteins. These results indicate potential roles for the LKB1/AMPK signaling axis to modify myofilament function, potentially though alterations in key post-translational modifications and protein-protein associations, in response to energetic stress. As such, targeting the LKB1/AMPK pathway could be beneficial in treating energetically impaired hearts.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/556039 |
| Date | January 2015 |
| Creators | Behunin, Samantha |
| Contributors | Konhilas, John, Granzier, Henk, Tardiff, Jil, Lynch, Ronald, Konhilas, John |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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