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Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle
The myosin super-relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with myosin-binding protein C (MyBP-C) in the sarcomere C-zone. To define how cardiac MyBP-C (cMyBP-C) and its specific domains contrib...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884578/ https://www.ncbi.nlm.nih.gov/pubmed/36688870 http://dx.doi.org/10.1085/jgp.202213276 |
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author | Nelson, Shane Beck-Previs, Samantha Sadayappan, Sakthivel Tong, Carl Warshaw, David M. |
author_facet | Nelson, Shane Beck-Previs, Samantha Sadayappan, Sakthivel Tong, Carl Warshaw, David M. |
author_sort | Nelson, Shane |
collection | PubMed |
description | The myosin super-relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with myosin-binding protein C (MyBP-C) in the sarcomere C-zone. To define how cardiac MyBP-C (cMyBP-C) and its specific domains contribute to stabilizing the SRX state in cardiac muscle, we took advantage of transgenic cMyBP-C null mice and those expressing cMyBP-C with a 271-residue N-terminal truncation. Utilizing super-resolution microscopy, we determined the lifetime and subsarcomeric location of individual fluorescent-ATP turnover events within isolated cardiac myofibrils. The proportion of SRX myosin demonstrated a gradient along the half-thick filament, highest in the P- and C-zones (72 ± 9% and 71 ± 6%, respectively) and lower in the D-zone (45 ± 10%), which lies farther from the sarcomere center and lacks cMyBP-C, suggesting a possible role for cMyBP-C in stabilizing the SRX. However, myofibrils from cMyBP-C null mice demonstrated an ∼40% SRX reduction, not only within the now cMyBP-C-free C-zone (49 ± 9% SRX), but also within the D-zone (22 ± 5% SRX). These data suggest that the influence of cMyBP-C on the SRX state is not limited to the C-zone but extends along the thick filament. Interestingly, myofibrils with N-terminal truncated cMyBP-C had an SRX content and spatial gradient similar to the cMyBP-C null, indicating that the N terminus of cMyBP-C is necessary for cMyBP-C’s role in enhancing the SRX gradient along the entire thick filament. Given that SRX myosin exist as a gradient along the thick filament that is highest in the C-zone, even in the absence of cMyBP-C or its N-terminus, an inherent bias must exist in the structure of the thick filament to stabilize the SRX state. |
format | Online Article Text |
id | pubmed-9884578 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-98845782023-07-23 Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle Nelson, Shane Beck-Previs, Samantha Sadayappan, Sakthivel Tong, Carl Warshaw, David M. J Gen Physiol Article The myosin super-relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with myosin-binding protein C (MyBP-C) in the sarcomere C-zone. To define how cardiac MyBP-C (cMyBP-C) and its specific domains contribute to stabilizing the SRX state in cardiac muscle, we took advantage of transgenic cMyBP-C null mice and those expressing cMyBP-C with a 271-residue N-terminal truncation. Utilizing super-resolution microscopy, we determined the lifetime and subsarcomeric location of individual fluorescent-ATP turnover events within isolated cardiac myofibrils. The proportion of SRX myosin demonstrated a gradient along the half-thick filament, highest in the P- and C-zones (72 ± 9% and 71 ± 6%, respectively) and lower in the D-zone (45 ± 10%), which lies farther from the sarcomere center and lacks cMyBP-C, suggesting a possible role for cMyBP-C in stabilizing the SRX. However, myofibrils from cMyBP-C null mice demonstrated an ∼40% SRX reduction, not only within the now cMyBP-C-free C-zone (49 ± 9% SRX), but also within the D-zone (22 ± 5% SRX). These data suggest that the influence of cMyBP-C on the SRX state is not limited to the C-zone but extends along the thick filament. Interestingly, myofibrils with N-terminal truncated cMyBP-C had an SRX content and spatial gradient similar to the cMyBP-C null, indicating that the N terminus of cMyBP-C is necessary for cMyBP-C’s role in enhancing the SRX gradient along the entire thick filament. Given that SRX myosin exist as a gradient along the thick filament that is highest in the C-zone, even in the absence of cMyBP-C or its N-terminus, an inherent bias must exist in the structure of the thick filament to stabilize the SRX state. Rockefeller University Press 2023-01-23 /pmc/articles/PMC9884578/ /pubmed/36688870 http://dx.doi.org/10.1085/jgp.202213276 Text en © 2023 Nelson et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Nelson, Shane Beck-Previs, Samantha Sadayappan, Sakthivel Tong, Carl Warshaw, David M. Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle |
title | Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle |
title_full | Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle |
title_fullStr | Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle |
title_full_unstemmed | Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle |
title_short | Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle |
title_sort | myosin-binding protein c stabilizes, but is not the sole determinant of srx myosin in cardiac muscle |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884578/ https://www.ncbi.nlm.nih.gov/pubmed/36688870 http://dx.doi.org/10.1085/jgp.202213276 |
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