Skeletal and Cardiac Muscle Contractile Activation: Tropomyosin “Rocks and Rolls”

Physiology ◽  
2001 ◽  
Vol 16 (2) ◽  
pp. 49-55 ◽  
Author(s):  
A. M. Gordon ◽  
M. Regnier ◽  
E. Homsher
Keyword(s):  
Cardiac Muscle ◽  
Thin Filament ◽  
Sarcomere Length ◽  
Force Development ◽  
Cross Bridge ◽  
Functional Differences ◽  
Filament Structure ◽  
Muscle Types ◽  
Contractile Activation ◽  
Muscle Contractile

Changes in thin filament structure induced by Ca2+ binding to troponin and subsequent strong cross-bridge binding regulate additional strong cross-bridge attachment, force development, and dependence of force on sarcomere length in skeletal and cardiac muscle. Variations in activation properties account for functional differences between these muscle types.

The Frank-Starling mechanism is not mediated by changes in rate of cross-bridge detachment

1997 ◽  
Vol 273 (5) ◽  
pp. H2428-H2435 ◽  
Author(s):  
Thomas Wannenburg ◽  
Paul M. L. Janssen ◽  
Dongsheng Fan ◽  
Pieter P. De Tombe
Keyword(s):  
Cardiac Muscle ◽  
Maximum Rate ◽  
Sarcomere Length ◽  
Myosin Head ◽  
Isometric Force ◽  
Force Development ◽  
Cross Bridge ◽  
Average Slope ◽  
The Cross ◽  
Kinetics Of

We tested the hypothesis that the Frank-Starling relationship is mediated by changes in the rate of cross-bridge detachment in cardiac muscle. We simultaneously measured isometric force development and the rate of ATP consumption at various levels of Ca2+ activation in skinned rat cardiac trabecular muscles at three sarcomere lengths (2.0, 2.1, and 2.2 μm). The maximum rate of ATP consumption was 1.5 nmol ⋅ s−1 ⋅ μl fiber vol−1, which represents an estimated adenosinetriphosphatase (ATPase) rate of ∼10 s−1 per myosin head at 24°C. The rate of ATP consumption was tightly and linearly coupled to the level of isometric force development, and changes in sarcomere length had no effect on the slope of the force-ATPase relationships. The average slope of the force-ATPase relationships was 15.5 pmol ⋅ mN−1 ⋅ mm−1. These results suggest that the mechanisms that underlie the Frank-Starling relationship in cardiac muscle do not involve changes in the kinetics of the apparent detachment step in the cross-bridge cycle.

scholarly journals Cross-Bridge versus Thin Filament Contributions to the Level and Rate of Force Development in Cardiac Muscle

2004 ◽  
Vol 87 (3) ◽  
pp. 1815-1824 ◽  
Author(s):  
M. Regnier ◽  
H. Martin ◽  
R.J. Barsotti ◽  
A.J. Rivera ◽  
D.A. Martyn ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Thin Filament ◽  
Rate Of Force Development ◽  
Force Development ◽  
Cross Bridge

scholarly journals Enhanced Ca2+ binding of cardiac troponin reduces sarcomere length dependence of contractile activation independently of strong crossbridges

2012 ◽  
Vol 303 (7) ◽  
pp. H863-H870 ◽  
Author(s):  
F. Steven Korte ◽  
Erik R. Feest ◽  
Maria V. Razumova ◽  
An-Yue Tu ◽  
Michael Regnier
Keyword(s):  
Cardiac Muscle ◽  
Cardiac Troponin ◽  
Thin Filament ◽  
Sarcomere Length ◽  
Calcium Sensitivity ◽  
Cardiac Troponin C ◽  
Filament Activation ◽  
Osmotic Compression ◽  
Butanedione Monoxime ◽  
Contractile Activation

Calcium sensitivity of the force-pCa relationship depends strongly on sarcomere length (SL) in cardiac muscle and is considered to be the cellular basis of the Frank-Starling law of the heart. SL dependence may involve changes in myofilament lattice spacing and/or myosin crossbridge orientation to increase probability of binding to actin at longer SLs. We used the L48Q cardiac troponin C (cTnC) variant, which has enhanced Ca2+ binding affinity, to test the hypotheses that the intrinsic properties of cTnC are important in determining 1) thin filament binding site availability and responsiveness to crossbridge activation and 2) SL dependence of force in cardiac muscle. Trabeculae containing L48Q cTnC-cTn lost SL dependence of the Ca2+ sensitivity of force. This occurred despite maintaining the typical SL-dependent changes in maximal force (Fmax). Osmotic compression of preparations at SL 2.0 μm with 3% dextran increased Fmax but not pCa50 in L48Q cTnC-cTn exchanged trabeculae, whereas wild-type (WT)-cTnC-cTn exchanged trabeculae exhibited increases in both Fmax and pCa50. Furthermore, crossbridge inhibition with 2,3-butanedione monoxime at SL 2.3 μm decreased Fmax and pCa50 in WT cTnC-cTn trabeculae to levels measured at SL 2.0 μm, whereas only Fmax was decreased with L48Q cTnC-cTn. Overall, these results suggest that L48Q cTnC confers reduced crossbridge dependence of thin filament activation in cardiac muscle and that changes in the Ca2+ sensitivity of force in response to changes in SL are at least partially dependent on properties of thin filament troponin.

scholarly journals Engineered Thin Filament Mutations to Study the Sarcomere Length Dependence of Cardiac Muscle Contractility

2018 ◽  
Vol 114 (3) ◽  
pp. 313a-314a
Author(s):  
Joseph D. Powers ◽  
Farid Moussavi-Harami ◽  
Jil C. Tardiff ◽  
Jennifer Davis ◽  
Michael Regnier
Keyword(s):  
Cardiac Muscle ◽  
Thin Filament ◽  
Sarcomere Length ◽  
Muscle Contractility ◽  
Length Dependence

scholarly journals The effect of altered temperature on Ca2(+)-sensitive force in permeabilized myocardium and skeletal muscle. Evidence for force dependence of thin filament activation.

1990 ◽  
Vol 96 (6) ◽  
pp. 1221-1245 ◽  
Author(s):  
N K Sweitzer ◽  
R L Moss
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Muscle ◽  
Thin Filament ◽  
Calcium Sensitivity ◽  
Differential Sensitivity ◽  
Fiber Types ◽  
Tension Development ◽  
Maximum Tension ◽  
Filament Activation ◽  
Muscle Types

The effect of changes in temperature on the calcium sensitivity of tension development was examined in permeabilized cellular preparations of rat ventricle and rabbit psoas muscle. Maximum force and Ca2+ sensitivity of force development increased with temperature in both muscle types. Cardiac muscle was more sensitive to changes in temperature than skeletal muscle in the range 10-15 degrees C. It was postulated that the level of thin filament activation may be decreased by cooling. To investigate this possibility, troponin C (TnC) was partially extracted from both muscle types, thus decreasing the level of thin filament activation independent of temperature and, at least in skeletal muscle fibers, decreasing cooperative activation of the thin filament as well. TnC extraction from cardiac muscle reduced the calcium sensitivity of tension less than did extraction of TnC from skeletal muscle. In skeletal muscle the midpoint shift of the tension-pCa curve with altered temperature was greater after TnC extraction than in control fibers. Calcium sensitivity of tension development was proportional to the maximum tension generated in cardiac or skeletal muscle under all conditions studied. Based on these results, we conclude that (a) maximum tension-generating capability and calcium sensitivity of tension development are related, perhaps causally, in fast skeletal and cardiac muscles, and (b) thin filament activation is less cooperative in cardiac muscle than in skeletal muscle, which explains the differential sensitivity of the two fiber types to temperature and TnC extraction. Reducing thin filament cooperativity in skeletal muscle by TnC extraction results in a response to temperature similar to that of control cardiac cells. This study provides evidence that force levels in striated muscle influence the calcium binding affinity of TnC.

scholarly journals I-Band Titin in Cardiac Muscle Is a Three-Element Molecular Spring and Is Critical for Maintaining Thin Filament Structure

1999 ◽  
Vol 146 (3) ◽  
pp. 631-644 ◽  
Author(s):  
Wolfgang A. Linke ◽  
Diane E. Rudy ◽  
Thomas Centner ◽  
Mathias Gautel ◽  
Christian Witt ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Thin Filament ◽  
Thick Filament ◽  
Cardiac Cells ◽  
Elastic Behavior ◽  
Unique Region ◽  
Cardiac Titin ◽  
Filament Structure ◽  
Pevk Domain ◽  
Cardiac Sarcomeres

In cardiac muscle, the giant protein titin exists in different length isoforms expressed in the molecule's I-band region. Both isoforms, termed N2-A and N2-B, comprise stretches of Ig-like modules separated by the PEVK domain. Central I-band titin also contains isoform-specific Ig-motifs and nonmodular sequences, notably a longer insertion in N2-B. We investigated the elastic behavior of the I-band isoforms by using single-myofibril mechanics, immunofluorescence microscopy, and immunoelectron microscopy of rabbit cardiac sarcomeres stained with sequence-assigned antibodies. Moreover, we overexpressed constructs from the N2-B region in chick cardiac cells to search for possible structural properties of this cardiac-specific segment. We found that cardiac titin contains three distinct elastic elements: poly-Ig regions, the PEVK domain, and the N2-B sequence insertion, which extends ∼60 nm at high physiological stretch. Recruitment of all three elements allows cardiac titin to extend fully reversibly at physiological sarcomere lengths, without the need to unfold Ig domains. Overexpressing the entire N2-B region or its NH2 terminus in cardiac myocytes greatly disrupted thin filament, but not thick filament structure. Our results strongly suggest that the NH2-terminal N2-B domains are necessary to stabilize thin filament integrity. N2-B–titin emerges as a unique region critical for both reversible extensibility and structural maintenance of cardiac myofibrils.

Myosin MgADP release rate decreases at longer sarcomere length to prolong myosin attachment time in skinned rat myocardium

2015 ◽  
Vol 309 (12) ◽  
pp. H2087-H2097 ◽  
Author(s):  
Bertrand C. W. Tanner ◽  
Jason J. Breithaupt ◽  
Peter O. Awinda
Keyword(s):  
Release Rate ◽  
Thin Filament ◽  
Molecular Mechanisms ◽  
Sarcomere Length ◽  
Cardiac Contractility ◽  
Force Production ◽  
Cross Bridge ◽  
Thin Filament Proteins ◽  
Filament Activation ◽  
Ventricular Filling

Cardiac contractility increases as sarcomere length increases, suggesting that intrinsic molecular mechanisms underlie the Frank-Starling relationship to confer increased cardiac output with greater ventricular filling. The capacity of myosin to bind with actin and generate force in a muscle cell is Ca2+ regulated by thin-filament proteins and spatially regulated by sarcomere length as thick-to-thin filament overlap varies. One mechanism underlying greater cardiac contractility as sarcomere length increases could involve longer myosin attachment time ( t on) due to slowed myosin kinetics at longer sarcomere length. To test this idea, we used stochastic length-perturbation analysis in skinned rat papillary muscle strips to measure t on as [MgATP] varied (0.05–5 mM) at 1.9 and 2.2 μm sarcomere lengths. From this t on-MgATP relationship, we calculated cross-bridge MgADP release rate and MgATP binding rates. As MgATP increased, t on decreased for both sarcomere lengths, but t on was roughly 70% longer for 2.2 vs. 1.9 μm sarcomere length at maximally activated conditions. These t on differences were driven by a slower MgADP release rate at 2.2 μm sarcomere length (41 ± 3 vs. 74 ± 7 s−1), since MgATP binding rate was not different between the two sarcomere lengths. At submaximal activation levels near the pCa50 value of the tension-pCa relationship for each sarcomere length, length-dependent increases in t on were roughly 15% longer for 2.2 vs. 1.9 μm sarcomere length. These changes in cross-bridge kinetics could amplify cooperative cross-bridge contributions to force production and thin-filament activation at longer sarcomere length and suggest that length-dependent changes in myosin MgADP release rate may contribute to the Frank-Starling relationship in the heart.

Effects of anisosmotic stress on cardiac muscle cell length, diameter, area, and sarcomere length

1996 ◽  
Vol 270 (4) ◽  
pp. H1414-H1422
Author(s):  
R. Tanaka ◽  
M. A. Barnes ◽  
G. Cooper ◽  
M. R. Zile
Keyword(s):  
Cardiac Muscle ◽  
Muscle Cell ◽  
Sarcomere Length ◽  
Cardiac Muscle Cell ◽  
Passive Stiffness ◽  
Future Studies ◽  
Percent Change ◽  
Cross Bridge ◽  
Butanedione Monoxime ◽  
Size Relation

The purpose of this study was to examine the effects of anisosmotic stress on adult mammalian cardiac muscle cell (cardiocyte) size. Cardiocyte size and sarcomere length were measured in cardiocytes isolated from 10 normal rats and 10 normal cats. Superfusate osmolarity was decreased from 300 +/- 6 to 130 +/- 5 mosM and increased to 630 +/- 8 mosM. Cardiocyte size and sarcomere length increased progressively when osmolarity was decreased, and there were no significant differences between cat and rat cardiocytes with respect to percent change in cardiocyte area or diameter; however, there were significant differences in cardiocyte length (2.8 +/- 0.3% in cat vs. 6.1 +/- 0.3% in rat, P < 0.05) and sarcomere length (3.3 +/- 0.3% in cat vs. 6.1 +/- 0.3% in rat, P < 0.05). To determine whether these species-dependent differences in length were related to diastolic interaction of the contractile elements or differences in relative passive stiffness, cardiocytes were subjected to the osmolarity gradient 1) during treatment with 7 mM 2,3-butanedione monoxime (BDM), which inhibits cross-bridge interaction, or 2) after pretreatment with 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N, N,N',N'-tetraacetic acid (EGTA), a bivalent Ca2+ chelator. Treatment with EGTA or BDM abolished the differences between cat and rat cardiocytes. Species-dependent differences therefore appeared to be related to the degree of diastolic cross-bridge association and not differences in relative passive stiffness. In conclusion, the osmolarity vs. cell size relation is useful in assessing the cardiocyte response to anisosmotic stress and may in future studies be useful in assessing changes in relative passive cardiocyte stiffness produced by pathological processes.

Regulation of Contraction in Striated Muscle

2000 ◽  
Vol 80 (2) ◽  
pp. 853-924 ◽  
Author(s):  
A. M. Gordon ◽  
E. Homsher ◽  
M. Regnier
Keyword(s):  
Binding Sites ◽  
Thin Filament ◽  
Striated Muscle ◽  
Force Development ◽  
Cross Bridge ◽  
Hydrolysis Products ◽  
Strong Binding ◽  
Regulation Of Contraction ◽  
Myosin Binding ◽  
Cross Bridges

Ca2+ regulation of contraction in vertebrate striated muscle is exerted primarily through effects on the thin filament, which regulate strong cross-bridge binding to actin. Structural and biochemical studies suggest that the position of tropomyosin (Tm) and troponin (Tn) on the thin filament determines the interaction of myosin with the binding sites on actin. These binding sites can be characterized as blocked (unable to bind to cross bridges), closed (able to weakly bind cross bridges), or open (able to bind cross bridges so that they subsequently isomerize to become strongly bound and release ATP hydrolysis products). Flexibility of the Tm may allow variability in actin (A) affinity for myosin along the thin filament other than through a single 7 actin:1 tropomyosin:1 troponin (A7TmTn) regulatory unit. Tm position on the actin filament is regulated by the occupancy of NH-terminal Ca2+binding sites on TnC, conformational changes resulting from Ca2+ binding, and changes in the interactions among Tn, Tm, and actin and as well as by strong S1 binding to actin. Ca2+ binding to TnC enhances TnC-TnI interaction, weakens TnI attachment to its binding sites on 1–2 actins of the regulatory unit, increases Tm movement over the actin surface, and exposes myosin-binding sites on actin previously blocked by Tm. Adjacent Tm are coupled in their overlap regions where Tm movement is also controlled by interactions with TnT. TnT also interacts with TnC-TnI in a Ca2+-dependent manner. All these interactions may vary with the different protein isoforms. The movement of Tm over the actin surface increases the “open” probability of myosin binding sites on actins so that some are in the open configuration available for myosin binding and cross-bridge isomerization to strong binding, force-producing states. In skeletal muscle, strong binding of cycling cross bridges promotes additional Tm movement. This movement effectively stabilizes Tm in the open position and allows cooperative activation of additional actins in that and possibly neighboring A7TmTn regulatory units. The structural and biochemical findings support the physiological observations of steady-state and transient mechanical behavior. Physiological studies suggest the following. 1) Ca2+ binding to Tn/Tm exposes sites on actin to which myosin can bind. 2) Ca2+ regulates the strong binding of M·ADP·Pi to actin, which precedes the production of force (and/or shortening) and release of hydrolysis products. 3) The initial rate of force development depends mostly on the extent of Ca2+ activation of the thin filament and myosin kinetic properties but depends little on the initial force level. 4) A small number of strongly attached cross bridges within an A7TmTn regulatory unit can activate the actins in one unit and perhaps those in neighboring units. This results in additional myosin binding and isomerization to strongly bound states and force production. 5) The rates of the product release steps per se (as indicated by the unloaded shortening velocity) early in shortening are largely independent of the extent of thin filament activation ([Ca2+]) beyond a given baseline level. However, with a greater extent of shortening, the rates depend on the activation level. 6) The cooperativity between neighboring regulatory units contributes to the activation by strong cross bridges of steady-state force but does not affect the rate of force development. 7) Strongly attached, cycling cross bridges can delay relaxation in skeletal muscle in a cooperative manner. 8) Strongly attached and cycling cross bridges can enhance Ca2+ binding to cardiac TnC, but influence skeletal TnC to a lesser extent. 9) Different Tn subunit isoforms can modulate the cross-bridge detachment rate as shown by studies with mutant regulatory proteins in myotubes and in in vitro motility assays. These results and conclusions suggest possible explanations for differences between skeletal and cardiac muscle regulation and delineate the paths future research may take toward a better understanding of striated muscle regulation.

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