Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle
Abstract
Nebulin is a giant sarcomeric protein that spans along the actin filament in skeletal muscle, from the Z-disk to near the thin filament pointed end. Mutations in nebulin cause muscle weakness in nemaline myopathy patients, suggesting that nebulin plays important roles in force generation, yet little is known about nebulin’s influence on thin filament structure and function. Here, we used small-angle X-ray diffraction and compared intact muscle deficient in nebulin (using a conditional nebulin-knockout, Neb cKO) with control (Ctrl) muscle. When muscles were activated, the spacing of the actin subunit repeat (27 Å) increased in both genotypes; when converted to thin filament stiffness, the obtained value was 30 pN/nm in Ctrl muscle and 10 pN/nm in Neb cKO muscle; that is, the thin filament was approximately threefold stiffer when nebulin was present. In contrast, the thick filament stiffness was not different between the genotypes. A significantly shorter left-handed (59 Å) thin filament helical pitch was found in passive and contracting Neb cKO muscles, as well as impaired tropomyosin and troponin movement. Additionally, a reduced myosin mass transfer toward the thin filament in contracting Neb cKO muscle was found, suggesting reduced cross-bridge interaction. Here, we conclude that nebulin is critically importantmore »
- Authors:
-
[1];
- Univ. of Arizona, Tucson, AZ (United States)
- Illinois Inst. of Technology, Chicago, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH); National Inst. of General Medical Sciences (NIGMS)
- OSTI Identifier:
- 1478092
- Grant/Contract Number:
- AC02-06CH11357; P41 GM103622; 1S10OD018090-01
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 115; Journal Issue: 41; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; X-ray diffraction; skeletal myopathy; muscle biology; physiology
Citation Formats
Kiss, Balázs, Lee, Eun-Jeong, Ma, Weikang, Li, Frank W., Tonino, Paola, Mijailovich, Srboljub M., Irving, Thomas C., and Granzier, Henk L. Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle. United States: N. p., 2018.
Web. doi:10.1073/pnas.1804726115.
Kiss, Balázs, Lee, Eun-Jeong, Ma, Weikang, Li, Frank W., Tonino, Paola, Mijailovich, Srboljub M., Irving, Thomas C., & Granzier, Henk L. Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle. United States. https://doi.org/10.1073/pnas.1804726115
Kiss, Balázs, Lee, Eun-Jeong, Ma, Weikang, Li, Frank W., Tonino, Paola, Mijailovich, Srboljub M., Irving, Thomas C., and Granzier, Henk L. Mon .
"Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle". United States. https://doi.org/10.1073/pnas.1804726115. https://www.osti.gov/servlets/purl/1478092.
@article{osti_1478092,
title = {Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle},
author = {Kiss, Balázs and Lee, Eun-Jeong and Ma, Weikang and Li, Frank W. and Tonino, Paola and Mijailovich, Srboljub M. and Irving, Thomas C. and Granzier, Henk L.},
abstractNote = {Nebulin is a giant sarcomeric protein that spans along the actin filament in skeletal muscle, from the Z-disk to near the thin filament pointed end. Mutations in nebulin cause muscle weakness in nemaline myopathy patients, suggesting that nebulin plays important roles in force generation, yet little is known about nebulin’s influence on thin filament structure and function. Here, we used small-angle X-ray diffraction and compared intact muscle deficient in nebulin (using a conditional nebulin-knockout, Neb cKO) with control (Ctrl) muscle. When muscles were activated, the spacing of the actin subunit repeat (27 Å) increased in both genotypes; when converted to thin filament stiffness, the obtained value was 30 pN/nm in Ctrl muscle and 10 pN/nm in Neb cKO muscle; that is, the thin filament was approximately threefold stiffer when nebulin was present. In contrast, the thick filament stiffness was not different between the genotypes. A significantly shorter left-handed (59 Å) thin filament helical pitch was found in passive and contracting Neb cKO muscles, as well as impaired tropomyosin and troponin movement. Additionally, a reduced myosin mass transfer toward the thin filament in contracting Neb cKO muscle was found, suggesting reduced cross-bridge interaction. Here, we conclude that nebulin is critically important for physiological force levels, as it greatly stiffens the skeletal muscle thin filament and contributes to thin filament activation and cross-bridge recruitment.},
doi = {10.1073/pnas.1804726115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 41,
volume = 115,
place = {United States},
year = {Mon Sep 24 00:00:00 EDT 2018},
month = {Mon Sep 24 00:00:00 EDT 2018}
}
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Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy
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Three-dimensional stochastic model of actin–myosin binding in the sarcomere lattice
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Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy
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- Brain, Vol. 136, Issue 6
Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency
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- Human Molecular Genetics, Vol. 18, Issue 13
Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy
journal, June 2015
- Li, Frank; Buck, Danielle; De Winter, Josine
- Human Molecular Genetics, Vol. 24, Issue 18
Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy
journal, June 2011
- Ochala, Julien; Lehtokari, Vilma-Lotta; Iwamoto, Hiroyuki
- The FASEB Journal, Vol. 25, Issue 6
The Filament Lattice of Striated Muscle
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Works referencing / citing this record:
Nebulin: big protein with big responsibilities
journal, January 2020
- Yuen, Michaela; Ottenheijm, Coen A. C.
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Nebulin and titin modulate cross-bridge cycling and length-dependent calcium sensitivity
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Nebulin no longer nebulous
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KBTBD13 is an actin-binding protein that modulates muscle kinetics
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Omecamtiv mecarbil lowers the contractile deficit in a mouse model of nebulin-based nemaline myopathy
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Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv
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Estimation of Forces on Actin Filaments in Living Muscle from X-ray Diffraction Patterns and Mechanical Data
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Nebulin and titin modulate cross-bridge cycling and length-dependent calcium sensitivity
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- The Journal of General Physiology, Vol. 151, Issue 5
Elastic domains of giant proteins in striated muscle: Modeling compliance with rulers
journal, April 2019
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- Journal of General Physiology, Vol. 151, Issue 5
Omecamtiv mecarbil lowers the contractile deficit in a mouse model of nebulin-based nemaline myopathy
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- Lindqvist, Johan; Lee, Eun-Jeong; Karimi, Esmat
- PLOS ONE, Vol. 14, Issue 11
Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv
journal, October 2019
- Lee, Eun-Jeong; Kolb, Justin; Hwee, Darren T.
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Estimation of Forces on Actin Filaments in Living Muscle from X-ray Diffraction Patterns and Mechanical Data
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