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dc.contributor.authorGrogan, Alyssa
dc.date.accessioned2021-02-08T15:46:07Z
dc.date.available2021-02-08T15:46:07Z
dc.date.issued2020
dc.identifier.urihttp://hdl.handle.net/10713/14500
dc.descriptionMolecular Medicine
dc.descriptionUniversity of Maryland, Baltimore
dc.descriptionPh.D.
dc.description.abstractObscurin (720-870 kDa) is a giant cytoskeletal protein that surrounds the periphery of myofibrils at M-bands and Z-disks where it plays key structural and regulatory roles in striated muscles. Immunoglobulin domains 58/59 (Ig58/59) of obscurin mediate binding to several important modulators of muscle structure and function, including canonical titin, a smaller splice isoform of titin termed novex-3, and phospholamban (PLN). Importantly, missense mutations identified within obscurin Ig58/59 that affect binding to titins and/or PLN are linked to cardiac and skeletal myopathies in humans. To assess the pathophysiological role of Ig58/59 in vivo, we generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59. Our studies revealed that young Obscn-ΔIg58/59 animals, which do not exhibit cardiac pathologies under sedentary conditions, experience tachycardia and severe arrhythmia following acute β-adrenergic stimulation and develop enlarged atria following prolonged exercise stress. Moreover, sedentary Obscn-ΔIg58/59 mice develop compensatory left ventricular hypertrophy that progresses to dilation, atrial enlargement, contractile dysfunction, and arrhythmia through aging in which males are more affected than females. Together, these findings demonstrate that deletion of obscurin Ig58/59 leads to both ventricular and atrial pathologies as a function of aging and in response to stress that manifest to different extents between sexes. We therefore aimed to decipher the cellular and molecular impact of the Ig58/59 deletion in Obscn-ΔIg58/59 ventricular and atrial myocardia, specifically focusing on males due to their enhanced disease severity. Our findings revealed that ventricular and atrial cardiomyocytes isolated from sedentary aging Obscn-ΔIg58/59 mice are enlarged and display tissue-specific alterations in Ca2+ cycling kinetics compared to controls, associated with distinct changes in the expression and phosphorylation status of major Ca2+ cycling proteins including PLN, the sarco-endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and the ryanodine receptor 2 (RyR2). Lastly, proteomics and phospho-proteomics studies conducted on aged Obscn-ΔIg58/59 atria revealed significant changes in the levels of cytoskeletal proteins, Ca2+ regulators, and Z-disk associated complexes. Taken together, our studies demonstrate that obscurin Ig58/59 is a key regulatory module in the heart, and its deletion leads to age- and sex-dependent cardiac remodeling and arrhythmia associated with tissue-specific molecular alterations in the ventricles and atria.
dc.subjectobscurinen_US
dc.subject.meshImmunoglobulin Domains--geneticsen_US
dc.subject.meshImmunoglobulin Domains--physiologyen_US
dc.titleInvestigating the pathophysiological significance of obscurin immunoglobulin domains Ig58/59 in the hearten_US
dc.typedissertationen_US
dc.date.updated2021-01-28T20:07:13Z
dc.language.rfc3066en
dc.contributor.advisorKontrogianni-Konstantopoulos, Aikaterini
dc.contributor.orcid0000-0002-1505-3311en_US
refterms.dateFOA2021-02-08T15:46:08Z


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