Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 module
IntroductionObscurin (720–870 kDa) is a giant cytoskeletal and signaling protein that possesses both structural and regulatory functions in striated muscles. Immunoglobulin domains 58/59 (Ig58/59) of obscurin bind to a diverse set of proteins that are essential for the proper structure and function...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1085840/full |
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| author | Alyssa Grogan Weiliang Huang Annie Brong Maureen A. Kane Aikaterini Kontrogianni-Konstantopoulos |
| author_facet | Alyssa Grogan Weiliang Huang Annie Brong Maureen A. Kane Aikaterini Kontrogianni-Konstantopoulos |
| author_sort | Alyssa Grogan |
| collection | DOAJ |
| description | IntroductionObscurin (720–870 kDa) is a giant cytoskeletal and signaling protein that possesses both structural and regulatory functions in striated muscles. Immunoglobulin domains 58/59 (Ig58/59) of obscurin bind to a diverse set of proteins that are essential for the proper structure and function of the heart, including giant titin, novex-3, and phospholamban (PLN). Importantly, the pathophysiological significance of the Ig58/59 module has been further underscored by the discovery of several mutations within Ig58/59 that are linked to various forms of myopathy in humans. We previously generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59, and characterized the effects of this deletion on cardiac morphology and function through aging. Our findings demonstrated that Obscn-ΔIg58/59 male animals develop severe arrhythmia, primarily manifesting as episodes of junctional escape and spontaneous loss of regular p-waves, reminiscent of human atrial fibrillation, accompanied by significant atrial enlargement that progresses in severity with aging.Methods and ResultsTo comprehensively characterize the molecular alterations responsible for these pathologies, we performed proteomic and phospho-proteomic analyses in aging Obscn-ΔIg58/59 atria. Our studies revealed extensive and novel alterations in the expression and phosphorylation profile of major cytoskeletal proteins, Ca2+ regulators, and Z-disk associated protein complexes in the Obscn-ΔIg58/59 atria through aging.DiscussionThese studies implicate obscurin, particularly the Ig58/59 module, as an essential regulator of the Z-disk associated cytoskeleton and Ca2+ cycling in the atria and provide new molecular insights into the development of atrial fibrillation and remodeling. |
| first_indexed | 2024-03-13T09:27:03Z |
| format | Article |
| id | doaj.art-43a7f9973aee416da0afaef2d5e76c96 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-03-13T09:27:03Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-43a7f9973aee416da0afaef2d5e76c962023-05-26T08:13:40ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-04-011010.3389/fcvm.2023.10858401085840Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 moduleAlyssa Grogan0Weiliang Huang1Annie Brong2Maureen A. Kane3Aikaterini Kontrogianni-Konstantopoulos4Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, United StatesDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United StatesDepartment of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, United StatesDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United StatesDepartment of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, United StatesIntroductionObscurin (720–870 kDa) is a giant cytoskeletal and signaling protein that possesses both structural and regulatory functions in striated muscles. Immunoglobulin domains 58/59 (Ig58/59) of obscurin bind to a diverse set of proteins that are essential for the proper structure and function of the heart, including giant titin, novex-3, and phospholamban (PLN). Importantly, the pathophysiological significance of the Ig58/59 module has been further underscored by the discovery of several mutations within Ig58/59 that are linked to various forms of myopathy in humans. We previously generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59, and characterized the effects of this deletion on cardiac morphology and function through aging. Our findings demonstrated that Obscn-ΔIg58/59 male animals develop severe arrhythmia, primarily manifesting as episodes of junctional escape and spontaneous loss of regular p-waves, reminiscent of human atrial fibrillation, accompanied by significant atrial enlargement that progresses in severity with aging.Methods and ResultsTo comprehensively characterize the molecular alterations responsible for these pathologies, we performed proteomic and phospho-proteomic analyses in aging Obscn-ΔIg58/59 atria. Our studies revealed extensive and novel alterations in the expression and phosphorylation profile of major cytoskeletal proteins, Ca2+ regulators, and Z-disk associated protein complexes in the Obscn-ΔIg58/59 atria through aging.DiscussionThese studies implicate obscurin, particularly the Ig58/59 module, as an essential regulator of the Z-disk associated cytoskeleton and Ca2+ cycling in the atria and provide new molecular insights into the development of atrial fibrillation and remodeling.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1085840/fullobscurinatrial fibrillationarrhythmiaZ-diskCa2+ cyclingcytoskeleton |
| spellingShingle | Alyssa Grogan Weiliang Huang Annie Brong Maureen A. Kane Aikaterini Kontrogianni-Konstantopoulos Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 module Frontiers in Cardiovascular Medicine obscurin atrial fibrillation arrhythmia Z-disk Ca2+ cycling cytoskeleton |
| title | Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 module |
| title_full | Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 module |
| title_fullStr | Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 module |
| title_full_unstemmed | Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 module |
| title_short | Alterations in cytoskeletal and Ca2+ cycling regulators in atria lacking the obscurin Ig58/59 module |
| title_sort | alterations in cytoskeletal and ca2 cycling regulators in atria lacking the obscurin ig58 59 module |
| topic | obscurin atrial fibrillation arrhythmia Z-disk Ca2+ cycling cytoskeleton |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1085840/full |
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