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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...

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Autores principales: Nelson, Shane, Beck-Previs, Samantha, Sadayappan, Sakthivel, Tong, Carl, Warshaw, David M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
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.
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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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