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dc.contributor.authorLynch, Thomas L. 4th
dc.contributor.authorLee, Kyounghwan
dc.contributor.authorCraig, Roger W.
dc.contributor.authorSadayappan, Sakthivel
dc.date2022-08-11T08:10:49.000
dc.date.accessioned2022-08-23T17:21:23Z
dc.date.available2022-08-23T17:21:23Z
dc.date.issued2021-03-26
dc.date.submitted2021-04-12
dc.identifier.citation<p>Lynch TL 4th, Kumar M, McNamara JW, Kuster DWD, Sivaguru M, Singh RR, Previs MJ, Lee KH, Kuffel G, Zilliox MJ, Lin BL, Ma W, Gibson AM, Blaxall BC, Nieman ML, Lorenz JN, Leichter DM, Leary OP, Janssen PML, de Tombe PP, Gilbert RJ, Craig R, Irving T, Warshaw DM, Sadayappan S. Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility. J Mol Cell Cardiol. 2021 Mar 26;156:33-44. doi: 10.1016/j.yjmcc.2021.03.009. Epub ahead of print. PMID: 33781820. <a href="https://doi.org/10.1016/j.yjmcc.2021.03.009">Link to article on publisher's site</a></p>
dc.identifier.issn0022-2828 (Linking)
dc.identifier.doi10.1016/j.yjmcc.2021.03.009
dc.identifier.pmid33781820
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48507
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractPhosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N')-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C(C0-C1f)), displayed dilated cardiomyopathy, underscoring the importance of the N'-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N'-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=33781820&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1016/j.yjmcc.2021.03.009
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCardiovascular System
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.titleAmino terminus of cardiac myosin binding protein-C regulates cardiac contractility
dc.typeJournal Article
dc.source.journaltitleJournal of molecular and cellular cardiology
dc.source.volume156
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/radiology_pubs/608
dc.identifier.contextkey22442996
html.description.abstract<p>Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N')-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C(C0-C1f)), displayed dilated cardiomyopathy, underscoring the importance of the N'-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N'-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.</p>
dc.identifier.submissionpathradiology_pubs/608
dc.contributor.departmentCraig Lab
dc.contributor.departmentDivision of Cell Biology and Imaging, Department of Radiology
dc.source.pages33-44


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