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Nebulin and titin modulate cross-bridge cycling and length-dependent calcium sensitivity

Journal Article · · Journal of General Physiology
 [1];  [2];  [2];  [2];  [3];  [4];  [5]
  1. Northeastern Univ., Boston, MA (United States); Illinois Inst. of Technology, Chicago, IL (United States)
  2. Univ. of Kragujevac (Serbia)
  3. Univ. of Kent (United Kingdom)
  4. Illinois Inst. of Technology, Chicago, IL (United States)
  5. Univ. of Arizona, Tucson, AZ (United States)
+ Show Author Affiliations

Various mutations in the structural proteins nebulin and titin that are present in human disease are known to affect the contractility of striated muscle. Loss of nebulin is associated with reduced actin filament length and impairment of myosin binding to actin, whereas titin is thought to regulate muscle passive elasticity and is likely involved in length-dependent activation. Here, we sought to assess the modulation of muscle function by these sarcomeric proteins by using the computational platform muscle simulation code (MUSICO) to quantitatively separate the effects of structural changes, kinetics of cross-bridge cycling, and calcium sensitivity of the thin filaments. The simulations show that variation in thin filament length cannot by itself account for experimental observations of the contractility in nebulin-deficient muscle, but instead must be accompanied by a decreased myosin binding rate. Additionally, to match the observed calcium sensitivity, the rate of TnI detachment from actin needed to be increased. Simulations for cardiac muscle provided quantitative estimates of the effects of different titin-based passive elasticities on muscle force and activation in response to changes in sarcomere length and interfilament lattice spacing. Predicted force–pCa relations showed a decrease in both active tension and sensitivity to calcium with a decrease in passive tension and sarcomere length. We conclude that this behavior is caused by partial redistribution of the muscle load between active muscle force and titin-dependent passive force, and also by redistribution of stretch along the thin filament, which together modulate the release of TnI from actin. These data help advance understanding of how nebulin and titin mutations affect muscle function.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); British Heart Foundation; European Research Council (ERC); Serbian Ministry of Science
OSTI ID:
1558308
Journal Information:
Journal of General Physiology, Journal Name: Journal of General Physiology Journal Issue: 5 Vol. 151; ISSN 0022-1295
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (135)

Nebulette: A 107 kD nebulin-like protein in cardiac muscle journal January 1995
SH3 in muscles: solution structure of the SH3 domain from nebulin journal February 1998
The myofilament elasticity and its effect on kinetics of force generation by the myosin motor journal June 2014
Modeling the Actin.myosin ATPase Cross-Bridge Cycle for Skeletal and Cardiac Muscle Myosin Isoforms journal March 2017
Computational simulation of hypertrophic cardiomyopathy mutations in Troponin I: Influence of increased myofilament calcium sensitivity on isometric force, ATPase and [Ca2+]i journal January 2007
A Simple Model with Myofilament Compliance Predicts Activation-Dependent Crossbridge Kinetics in Skinned Skeletal Fibers journal December 2002
Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments journal March 1995
Compliant Realignment of Binding Sites in Muscle: Transient Behavior and Mechanical Tuning journal April 1998
Variation of thin filament length in heart muscle journal May 1977
Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments journal November 2015
Myosin filament activation in the heart is tuned to the mechanical task journal March 2017
Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle journal September 2018
Titin: major myofibrillar components of striated muscle. journal August 1979
Identification of an N2 line protein of striated muscle. journal June 1980
Evidence for cross-bridge attachment in relaxed muscle at low ionic strength. journal December 1982
Molecular Mechanics of Cardiac Titin's PEVK and N2B Spring Elements journal March 2002
Nebulin increases thin filament stiffness and force per cross-bridge in slow-twitch soleus muscle fibers journal October 2018
Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency journal April 2009
Connectin, an Elastic Protein of Muscle. Identification of “Titin” with Connectin1 journal January 1981
Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I journal September 2016
Mechanically Driven Contour-Length Adjustment in Rat Cardiac Titin’s Unique N2B Sequence: Titin Is an Adjustable Spring journal June 1999
Filament Compliance Influences Cooperative Activation of Thin Filaments and the Dynamics of Force Production in Skeletal Muscle journal May 2012
Thick Filament Mechano-Sensing in Skeletal and Cardiac Muscles: A Common Mechanism Able to Adapt the Energetic Cost of the Contraction to the Task journal June 2018
Distinct contributions of the thin and thick filaments to length-dependent activation in heart muscle journal February 2017
Mechanical properties of tropomyosin and implications for muscle regulation journal January 1996
Mechanical properties of tropomyosin and implications for muscle regulation journal January 1996
Congenital Titinopathy: Comprehensive characterization and pathogenic insights journal May 2018
X-ray diffraction from striated muscles and nerves in normal and dystrophic mice journal March 1982
Refinement of the F-Actin Model against X-ray Fiber Diffraction Data by the Use of a Directed Mutation Algorithm journal December 1993
Tropomyosin Length and Two-stranded F-actin Flexibility in the Thin Filament journal October 1994
Steric-model for activation of muscle thin filaments 1 1 Edited by P.E. Wright journal February 1997
Titin and the sarcomere symmetry paradox11Edited by J. Karn journal January 2001
Cooperative regulation of myosin-S1 binding to actin filaments by a continuous flexible Tm–Tn chain journal October 2012
Sarcomere-length dependence of lattice volume and radial mass transfer of myosin cross-bridges in rat papillary muscle journal May 2004
Titin-based modulation of active tension and interfilament lattice spacing in skinned rat cardiac muscle journal November 2004
Titin/connectin-based modulation of the Frank-Starling mechanism of the heart journal February 2006
The role of super-relaxed myosin in skeletal and cardiac muscle journal December 2014
Calcium binding to cardiac troponin C journal March 1978
The amino acid sequence of bovine cardiac troponin-C. Comparison with rabbit skeletal troponin-C journal May 1975
Evidence that nebulin is a protein-ruler in muscle thin filaments journal May 1991
Cooperative Regulation of Myosin-Actin Interactions by a Continuous Flexible Chain I: Actin-Tropomyosin Systems journal May 2003
Cooperative Regulation of Myosin-Actin Interactions by a Continuous Flexible Chain II: Actin-Tropomyosin-Troponin and Regulation by Calcium journal May 2003
Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament journal August 1993
The force exerted by a single kinesin molecule against a viscous load journal August 1994
X-ray diffraction measurements of the extensibility of actin and myosin filaments in contracting muscle journal December 1994
X-ray diffraction evidence for the extensibility of actin and myosin filaments during muscle contraction journal December 1994
Compliance of thin filaments in skinned fibers of rabbit skeletal muscle journal September 1995
Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments journal March 1995
Myosin binding-induced cooperative activation of the thin filament in cardiac myocytes and skeletal muscle fibers journal April 1995
Compliant Realignment of Binding Sites in Muscle: Transient Behavior and Mechanical Tuning journal April 1998
The Stiffness of Skeletal Muscle in Isometric Contraction and Rigor: The Fraction of Myosin Heads Bound to Actin journal May 1998
Extensibility and Symmetry of Actin Filaments in Contracting Muscles journal December 1999
Proteolytic fragments of troponin C. Localization of high and low affinity Ca2+ binding sites and interactions with troponin I and troponin T journal August 1978
The calcium and magnesium binding sites on troponin and their role in the regulation of myofibrillar adenosine triphosphatase. journal June 1975
The calcium and magnesium binding sites on cardiac troponin and their role in the regulation of myofibrillar adenosine triphosphatase. journal December 1980
The Complete Mouse Nebulin Gene Sequence and the Identification of Cardiac Nebulin journal May 2003
Brownian motion in a field of force and the diffusion model of chemical reactions journal April 1940
Architecture and function in the muscle sarcomere journal April 1997
Interactions Between Connected Half-Sarcomeres Produce Emergent Mechanical Behavior in a Mathematical Model of Muscle journal January 2010
Electron Microscopy and Persistence Length Analysis of Semi-Rigid Smooth Muscle Tropomyosin Strands journal August 2010
Cooperative [Ca2+]-Dependent Regulation of the Rate of Myosin Binding to Actin: Solution Data and the Tropomyosin Chain Model journal June 2011
Regulation of Contraction by the Thick Filaments in Skeletal Muscle journal December 2017
Resolution and uniqueness of estimated parameters of a model of thin filament regulation in solution journal February 2010
Single Particle Analysis of Relaxed and Activated Muscle Thin Filaments journal February 2005
Understanding the Organisation and Role of Myosin Binding Protein C in Normal Striated Muscle by Comparison with MyBP-C Knockout Cardiac Muscle journal December 2008
The Shape and Flexibility of Tropomyosin Coiled Coils: Implications for Actin Filament Assembly and Regulation journal January 2010
The Hill Model for Binding Myosin S1 to Regulated Actin Is not Equivalent to the McKillop–Geeves Model journal March 2012
A comparison of muscle thin filament models obtained from electron microscopy reconstructions and low-angle X-ray fibre diagrams from non-overlap muscle journal August 2006
Altered myofilament function depresses force generation in patients with nebulin-based nemaline myopathy (NEM2) journal May 2010
The relationship between curvature, flexibility and persistence length in the tropomyosin coiled-coil journal May 2010
Genotype?phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle ?-actin journal September 2004
Titin-based tension in the cardiac sarcomere: Molecular origin and physiological adaptations journal October 2012
Myofilament length dependent activation journal May 2010
Thin filament length in the cardiac sarcomere varies with sarcomere length but is independent of titin and nebulin journal August 2016
Cooperativity and Switching within the Three-State Model of Muscle Regulation † journal January 1999
Proposed Mechanism of Force Generation in Striated Muscle journal October 1971
Structure of co-crystals of tropomyosin and troponin journal February 1987
Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy journal January 2002
Role of titin in cardiomyopathy: from DNA variants to patient stratification journal December 2017
Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo journal August 2006
Truncations of Titin Causing Dilated Cardiomyopathy journal February 2012
Titin strain contributes to the Frank–Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins journal February 2016
Direct measurement of stiffness of single actin filaments with and without tropomyosin by in vitro nanomanipulation. journal December 1994
Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy journal March 1999
Molecular model of muscle contraction journal March 1999
Nebulin Alters Cross-bridge Cycling Kinetics and Increases Thin Filament Activation: A NOVEL MECHANISM FOR INCREASING TENSION AND REDUCING TENSION COST journal September 2009
Single Molecule Force Spectroscopy on Titin Implicates Immunoglobulin Domain Stability as a Cardiac Disease Mechanism journal January 2013
Dilated cardiomyopathy myosin mutants have reduced force-generating capacity journal April 2018
Nebulin as a length regulator of thin filaments of vertebrate skeletal muscles: correlation of thin filament length, nebulin size, and epitope profile journal October 1991
Titin Extensibility In Situ: Entropic Elasticity of Permanently Folded and Permanently Unfolded Molecular Segments journal February 1998
Titin Determines the Frank-Starling Relation in Early Diastole journal January 2003
Mouse intact cardiac myocyte mechanics: cross-bridge and titin-based stress in unactivated cells journal December 2010
Three-dimensional stochastic model of actin–myosin binding in the sarcomere lattice journal November 2016
Sizes of components in frog skeletal muscle measured by methods of stereology journal July 1975
Path-integral theory of an axially confined worm-like chain journal May 2001
Visualization of cardiac muscle thin filaments and measurement of their lengths by electron tomography journal January 2008
Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy journal June 2015
A Spatially Explicit Model Shows How Titin Stiffness Modulates Muscle Mechanics and Energetics journal June 2018
Sarcoplasmic reticulum calcium uptake and speed of relaxation are depressed in nebulin-free skeletal muscle journal August 2008
Nebulin plays a direct role in promoting strong actin-myosin interactions journal December 2009
Nebulin, a major player in muscle health and disease journal March 2011
Cardiac Titin and Heart Disease journal January 2014
The length–tension curve in muscle depends on lattice spacing journal September 2013
Elasticity of α -Helical Coiled Coils journal December 2006
X-ray diffraction from nonuniformly stretched helical molecules journal April 2016
The measurement and dynamic implications of thin filament lengths in heart muscle. journal January 1979
Titin Isoform Variance and Length Dependence of Activation in Skinned Bovine Cardiac Muscle journal November 2003
A Spatially Explicit Nanomechanical Model of the Half-Sarcomere: Myofilament Compliance Affects Ca 2+ -Activation journal November 2004
Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy journal August 2015
Length, force, and Ca(2+)-troponin C affinity in cardiac and slow skeletal muscle journal April 1994
Myofilament lattice spacing as a function of sarcomere length in isolated rat myocardium journal November 2000
The Filament Lattice of Striated Muscle journal April 1998
Regulation of Contraction in Striated Muscle journal January 2000
Roles of Titin in the Structure and Elasticity of the Sarcomere journal January 2010
Length-dependent activation: its effect on the length-tension relation in cat ventricular muscle. journal March 1977
Comparison between the sarcomere length-force relations of intact and skinned trabeculae from rat right ventricle. Influence of calcium concentrations on these relations. journal June 1986
Mechanically Driven Contour-Length Adjustment in Rat Cardiac Titin’s Unique N2B Sequence: Titin Is an Adjustable Spring journal June 1999
Differential Expression of Cardiac Titin Isoforms and Modulation of Cellular Stiffness journal January 2000
Truncation of Titin’s Elastic PEVK Region Leads to Cardiomyopathy With Diastolic Dysfunction journal September 2009
Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes journal August 2011
Shortening of the Elastic Tandem Immunoglobulin Segment of Titin Leads to Diastolic Dysfunction journal July 2013
Titin Is a Major Human Disease Gene journal February 2013
Experimentally Increasing Titin Compliance in a Novel Mouse Model Attenuates the Frank-Starling Mechanism But Has a Beneficial Effect on Diastole journal May 2014
Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction journal October 2016
Role of Titin Missense Variants in Dilated Cardiomyopathy journal October 2015
Titin-Based Modulation of Calcium Sensitivity of Active Tension in Mouse Skinned Cardiac Myocytes journal May 2001
Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy journal January 2011
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy journal August 2013
The Giant Muscle Protein Titin is an Adjustable Molecular Spring journal January 2006
Interactions between Connected Half-Sarcomeres Produce Emergent Mechanical Behavior in a Mathematical Model of Muscle journal November 2009
Persistence Length of Human Cardiac α-Tropomyosin Measured by Single Molecule Direct Probe Microscopy journal June 2012
Fast Skeletal Muscle Troponin Activation Increases Force of Mouse Fast Skeletal Muscle and Ameliorates Weakness Due to Nebulin-Deficiency journal February 2013
Effects of cross-bridge compliance on the force-velocity relationship and muscle power output journal December 2017
The Sarcomeric Protein Nebulin: Another Multifunctional Giant in Charge of Muscle Strength Optimization journal January 2012
Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle journal September 2018

Cited By (7)

Nebulin: big protein with big responsibilities journal January 2020
Progress on the regulation of myofibrillar function: Part 2 journal April 2019
Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function journal January 2020
Estimation of Forces on Actin Filaments in Living Muscle from X-ray Diffraction Patterns and Mechanical Data journal November 2019
Calcium-dependent titin–thin filament interactions in muscle: observations and theory journal July 2019
Elastic domains of giant proteins in striated muscle: Modeling compliance with rulers journal April 2019
The mechanism of thin filament regulation: Models in conflict? journal September 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Contraction and Cell Motility
Myofilament Function