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.
Skip Nav Destination
Article navigation
Article|
Myofilament Function 2022|
January 23 2023
Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle
Shane Nelson
,
Shane Nelson
1
Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, University of Vermont
, Burlington, VT, USA
Search for other works by this author on:
Samantha Beck-Previs
,
Samantha Beck-Previs
1
Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, University of Vermont
, Burlington, VT, USA
Search for other works by this author on:
Sakthivel Sadayappan
,
Sakthivel Sadayappan
2
Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati
, Cincinnati, OH, USA
Search for other works by this author on:
Carl Tong,
Carl Tong
3
Department of Medical Physiology, Texas A&M University
, Bryan, TX, USA
Search for other works by this author on:
David M. Warshaw
1
Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, University of Vermont
, Burlington, VT, USA
Correspondence to David M. Warshaw: david.warshaw@med.uvm.edu
Search for other works by this author on:
Shane Nelson
1
Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, University of Vermont
, Burlington, VT, USA
Samantha Beck-Previs
1
Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, University of Vermont
, Burlington, VT, USA
Sakthivel Sadayappan
2
Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati
, Cincinnati, OH, USA
Carl Tong
3
Department of Medical Physiology, Texas A&M University
, Bryan, TX, USA
Correspondence to David M. Warshaw: david.warshaw@med.uvm.edu
This work is part of a special issue on Myofilament Function 2022.
Received:
October 05 2022
Revision Received:
December 08 2022
Accepted:
January 03 2023
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding
Funder(s):
National Institutes of Health
- Award Id(s): HL150953,R01 AR078001,R01 HL130356,R01 HL105826,R38 HL155775,R01 HL143490
Funder(s):
American Heart Association
- Award Id(s): 19UFEL34380251
Funder(s):
PLN Foundation
Funder(s):
Fondation Leducq
- Award Id(s): 18CVD01
© 2023 Nelson et al.
2023
Nelson et al.
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/).
J Gen Physiol (2023) 155 (4): e202213276.
Article history
Received:
October 05 2022
Revision Received:
December 08 2022
Accepted:
January 03 2023
Citation
Shane Nelson, Samantha Beck-Previs, Sakthivel Sadayappan, Carl Tong, David M. Warshaw; Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle. J Gen Physiol 3 April 2023; 155 (4): e202213276. doi: https://doi.org/10.1085/jgp.202213276
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Sign in via your Institution
Sign in via your Institution
126
Views
Suggested Content
Single-molecule imaging reveals how mavacamten and PKA modulate ATP turnover in skeletal muscle myofibrils
J Gen Physiol (November,2022)
Advertisement