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Study of Cardiac Function and Energetics in Mouse Models of Cardiomyopathies by MRI and NMR Spectroscopy

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2010, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.

Cardiovascular diseases are the leading cause of death and a major cause of disability in the United States. Specific genetic mutations can lead to profound cardiac functional and metabolic alterations, representing a major cause of cardiomyopathy and heart failure. This thesis project focused on the study of cardiac function and energetics in mouse models with dystrophin-related cardiomyopathies using state-of-the-art MRI and NMR spectroscopic methods.

Dystrophin belongs to the trans-membrane dystrophin-glycoprotein complex (DGC). DGC plays an important role in maintaining the structural integrity of muscle fibers by linking the intracellular cytoskeleton to the extracellular matrix. The disruption of DGC structure due to dystrophin deficiency can lead to Duchenne muscular dystrophy (DMD) with progressive skeletal muscle wasting and frequent cardiac involvement.

We evaluated the cardiac functional alterations in dystrophin-deficient mdx mice, a model of DMD, using 3D MR tagging. While mdx mice showed a progressive decline in cardiac function longitudinally, young mdx mice showed an unexpected increase in myocardial contractility. Since DGC-associated neuronal nitric oxide synthase (nNOS) is also impaired, we hypothesized that the increased left ventricular function in young mdx mice is due to disrupted DGC-associated nNOS signaling.

To evaluate the role of DGC-associated nNOS, we characterized α-dystrobrevin knockout (adbn-/-) mice, which have maintained DGC structure but impaired DGC-associated nNOS signaling. We developed an image processing method for accurate quantification of myocardial wall motion in mice by MRI tagging. At baseline, young adbn-/- mice also showed increased myocardial contractility in vivo, associated with increased myocyte contractility, calcium transient and L-type calcium current in vitro. These results indicated the role of DGC-associated nNOS in regulating basal cardiac function through the inhibition of L-type calcium channel.

We developed a 13C isotopomer model for quantification of substrate utilization and anaplerosis using both NMR and mass spectrometry. Adbn-/- mice showed increased glucose and lactate utilization but maintained fatty utilization and anaplerosis, suggesting the role of DGC-associated nNOS in regulation of cardiac metabolism.

To summarize, MRI tagging and 13C-NMR spectroscopy are powerful tools for cardiac functional and metabolic phenotyping in mice; DGC-associated nNOS plays important roles in regulation of both cardiac function and energy metabolism.

Xin Yu (Advisor)
Gerald Saidel (Committee Member)
Margaret Chandler (Committee Member)
David Van Wagoner (Committee Member)
133 p.

Recommended Citations

Citations

  • Li, W. (2010). Study of Cardiac Function and Energetics in Mouse Models of Cardiomyopathies by MRI and NMR Spectroscopy [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1269983160

    APA Style (7th edition)

  • Li, Wei. Study of Cardiac Function and Energetics in Mouse Models of Cardiomyopathies by MRI and NMR Spectroscopy. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1269983160.

    MLA Style (8th edition)

  • Li, Wei. "Study of Cardiac Function and Energetics in Mouse Models of Cardiomyopathies by MRI and NMR Spectroscopy." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1269983160

    Chicago Manual of Style (17th edition)