Show simple item record

dc.contributor.advisorKonhilas, Johnen
dc.contributor.authorBehunin, Samantha
dc.creatorBehunin, Samanthaen
dc.date.accessioned2015-05-29T17:30:04Zen
dc.date.available2015-05-29T17:30:04Zen
dc.date.issued2015en
dc.identifier.urihttp://hdl.handle.net/10150/556039en
dc.description.abstractHeart 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.
dc.language.isoen_USen
dc.publisherThe University of Arizona.en
dc.rightsCopyright © 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.en
dc.subjectPhysiological Sciencesen
dc.titleLiver Kinase B1 and AMP-Activated Protein Kinase Regulation of Sarcomeric Function in the Rodent Hearten_US
dc.typetexten
dc.typeElectronic Dissertationen
thesis.degree.grantorUniversity of Arizonaen
thesis.degree.leveldoctoralen
dc.contributor.committeememberGranzier, Henken
dc.contributor.committeememberTardiff, Jilen
dc.contributor.committeememberLynch, Ronalden
dc.contributor.committeememberKonhilas, Johnen
dc.description.releaseRelease after 23-Mar-2016en
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplinePhysiological Sciencesen
thesis.degree.namePh.D.en
refterms.dateFOA2016-03-23T00:00:00Z
html.description.abstractHeart 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.


Files in this item

Thumbnail
Name:
azu_etd_13799_sip1_m.pdf
Size:
5.605Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record