Coupling calcium binding to troponin C and cross-bridge cycling in skinned cardiac cells

1994 ◽  
Vol 266 (3) ◽  
pp. H1260-H1271 ◽  
Author(s):  
A. Landesberg ◽  
S. Sideman
Keyword(s):  
Cardiac Muscle ◽  
Calcium Binding ◽  
Troponin C ◽  
Cardiac Cells ◽  
Loose Coupling ◽  
Cross Bridge ◽  
Length Relationship ◽  
Troponin Complex ◽  
Cross Bridges

This study examines the coupling of calcium binding to troponin with the force developed by the cross bridges in the skinned cardiac muscle. It emphasizes the key role of the troponin complex in regulating cross-bridge cycling and defines four distinct states of the troponin complex in the single-overlap region. These include a "loose-coupling" state, wherein cross bridges can exist in the strong conformation without having calcium bound to the neighbor troponin C. Published simultaneous measurements of the force and the bound calcium are used to calculate the apparent calcium binding coefficients. The force-length relationships at different free calcium concentrations are used to evaluate the cooperative mechanism. The dependence of the affinity of troponin for calcium on the number of force-generating cross bridges is the dominant cooperative mechanism. The proposed loose-coupling model, with a positive feedback of force on calcium binding, describes the role of calcium in force regulation and the force-length relationship in skinned cardiac muscle. The ability to simulate the rate of force development is demonstrated.

Effect of length and cross-bridge attachment on Ca2+ binding to cardiac troponin C

1987 ◽  
Vol 253 (1) ◽  
pp. C90-C96 ◽  
Author(s):  
P. A. Hofmann ◽  
F. Fuchs
Keyword(s):  
Cardiac Muscle ◽  
Cardiac Troponin ◽  
Sarcomere Length ◽  
Troponin C ◽  
Saturation Curve ◽  
Cross Bridge ◽  
Cardiac Troponin C ◽  
Length Dependence ◽  
Length Relationship ◽  
Cross Bridges

The sensitivity of skinned cardiac muscle bundles to Ca2+ is a function of sarcomere length. Ca2+ sensitivity is increased as fiber length is extended along the ascending limb of the force-length curve and it has been suggested that this phenomenon makes a major contribution to the steep force-length relationship that exists in living cardiac muscle. To gain greater insight into the mechanism behind the length dependence of Ca2+ sensitivity isotopic measurements of Ca2+ binding to detergent-extracted bovine, ventricular muscle bundles were made under conditions in which troponin C was the only major Ca2+ binding species. Experiments were designed to determine whether 1) Ca2+-troponin C affinity varies in the sarcomere length range corresponding to the ascending limb of the force-length curve, and 2) Ca2+ binding correlates with length per se or with changes in the number of length-dependent cross-bridge attachments. Measurements were made of Ca2+ binding in the rigor and relaxed states. The latter state was produced by suppressing actin-myosin interaction with the phosphate analogue, sodium vanadate. After vanadate treatment it is possible to obtain a complete Ca2+ saturation curve in the presence of physiological MgATP concentrations and at constant sarcomere length. The results show that the binding of Ca2+ to the regulatory site of cardiac troponin C is length dependent but this length dependence is actually a dependence on the number of attached cross bridges.

Regulation of energy consumption in cardiac muscle: analysis of isometric contractions

1999 ◽  
Vol 276 (3) ◽  
pp. H998-H1011 ◽  
Author(s):  
Amir Landesberg ◽  
Samuel Sideman
Keyword(s):  
Energy Consumption ◽  
Cardiac Muscle ◽  
Feedback Mechanism ◽  
Isometric Contractions ◽  
Cross Bridge ◽  
Time Integral ◽  
Length Relationship ◽  
Cross Bridges ◽  
Force Time ◽  
Force Time Integral

The well-known linear relationship between oxygen consumption and force-length area or the force-time integral is analyzed here for isometric contractions. The analysis, which is based on a biochemical model that couples calcium kinetics with cross-bridge cycling, indicates that the change in the number of force-generating cross bridges with the change in the sarcomere length depends on the force generated by the cross bridges. This positive-feedback phenomenon is consistent with our reported cooperativity mechanism, whereby the affinity of the troponin for calcium and, hence, cross-bridge recruitment depends on the number of force-generating cross bridges. Moreover, it is demonstrated that a model that does not include a feedback mechanism cannot describe the dependence of energy consumption on the loading conditions. The cooperativity mechanism, which has been shown to determine the force-length relationship and the related Frank-Starling law, is shown here to provide the basis for the regulation of energy consumption in the cardiac muscle.

Mechanical regulation of cardiac muscle by coupling calcium kinetics with cross-bridge cycling: a dynamic model

1994 ◽  
Vol 267 (2) ◽  
pp. H779-H795 ◽  
Author(s):  
A. Landesberg ◽  
S. Sideman
Keyword(s):  
Cardiac Muscle ◽  
Calcium Binding ◽  
Mechanical Activity ◽  
Free Calcium ◽  
Shortening Velocity ◽  
Cross Bridge ◽  
Mechanical Constraints ◽  
Force Velocity ◽  
Cross Bridges ◽  
Reported Data

This study describes the regulation of mechanical activity in the intact cardiac muscle, the effects of the free calcium transients and the mechanical constraints, and emphasizes the central role of the troponin complex in regulating muscle activity. A “loose coupling” between calcium binding to troponin and cross-bridge cycling is stipulated, allowing the existence of cross bridges in the strong conformation without having bound calcium on the neighboring troponin. The model includes two feedback mechanisms: 1) a positive feedback, or cooperativity, in which the cycling cross bridges affect the affinity of troponin for calcium, and 2) a negative mechanical feedback, where the filament-sliding velocity affects cross-bridge cycling. The model simulates the reported experimental force-length and force-velocity relationships at different levels of activation. The dependence of the shortening velocity on calcium concentration, sarcomere length, internal load, and rate of cross-bridge cycling is described analytically in agreement with reported data. Furthermore, the model provides an analytic solution for Hill's equation of the force-velocity relationship and for the phenomena of unloaded shortening velocity and force deficit. The model-calculated changes in free calcium in various mechanical conditions are in good agreement with the available experimental results.

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities

2007 ◽  
Vol 293 (4) ◽  
pp. H2580-H2587 ◽  
Author(s):  
Catalina Norman ◽  
Jack A. Rall ◽  
Svetlana B. Tikunova ◽  
Jonathan P. Davis
Keyword(s):  
Muscle Contraction ◽  
Cardiac Muscle ◽  
Calcium Binding ◽  
Force Production ◽  
Troponin C ◽  
Binding Affinities ◽  
Cardiac Muscle Contraction ◽  
Cross Bridge ◽  
Original Length ◽  
Physiological Relevance

We investigated whether changing thin filament Ca2+ sensitivity alters the rate of contraction, either during normal cross-bridge cycling or when cross-bridge cycling is increased by inorganic phosphate (Pi). We increased or decreased Ca2+ sensitivity of force production by incorporating into rat skinned cardiac trabeculae the troponin C (TnC) mutants V44QTnCF27W and F20QTnCF27W. The rate of isometric contraction was assessed as the rate of force redevelopment ( ktr) after a rapid release and restretch to the original length of the muscle. Both in the absence of added Pi and in the presence of 2.5 mM added Pi 1) Ca2+ sensitivity of ktr was increased by V44QTnCF27W and decreased by F20QTnCF27W compared with control TnCF27W; 2) ktr at submaximal Ca2+ activation was significantly faster for V44QTnCF27W and slower for F20QTnCF27W compared with control TnCF27W; 3) at maximum Ca2+ activation, ktr values were similar for control TnCF27W, V44QTnCF27W, and F20QTnCF27W; and 4) ktr exhibited a linear dependence on force that was indistinguishable for all TnCs. In the presence of 2.5 mM Pi, ktr was faster at all pCa values compared with the values for no added Pi for TnCF27W, V44QTnCF27W, and F20QTnCF27W. This study suggests that TnC Ca2+ binding properties modulate the rate of cardiac muscle contraction at submaximal levels of Ca2+ activation. This result has physiological relevance considering that, on a beat-to-beat basis, the heart contracts at submaximal Ca2+ activation.

scholarly journals Stretch of active muscle during the declining phase of the calcium transient produces biphasic changes in calcium binding to the activating sites.

1990 ◽  
Vol 96 (5) ◽  
pp. 1013-1035 ◽  
Author(s):  
A M Gordon ◽  
E B Ridgway
Keyword(s):  
Calcium Binding ◽  
Time Course ◽  
Control Level ◽  
Calcium Transient ◽  
Length Change ◽  
Positive Phase ◽  
Active Force ◽  
Cross Bridge ◽  
Calcium Affinity ◽  
Cross Bridges

In voltage-clamped barnacle single muscle fibers, muscle shortening during the declining phase of the calcium transient increases myoplasmic calcium. This extra calcium is probably released from the activating sites by a change in affinity when cross-bridges break (Gordon, A. M., and E. B. Ridgway, 1987. J. Gen. Physiol. 90:321-340). Stretching the muscle at similar times causes a more complex response, a rapid increase in intracellular calcium followed by a transient decrease. The amplitudes of both phases increase with the rate and amplitude of stretch. The rapid increase, however, appears only when the muscle is stretched more than approximately 0.4%. This is above the length change that produces the breakpoint in the force record during a ramp stretch. This positive phase in response to large stretches is similar to that seen on equivalent shortening at the same point in the contraction. For stretches at different times during the calcium transient, the peak amplitude of the positive phase has a time course that is delayed relative to the calcium transient, while the peak decrease during the negative phase has an earlier time course that is more similar to the calcium transient. The amplitudes of both phases increase with increasing strength of stimulation and consequent force. When the initial muscle the active force. A large decrease in length (which drops the active force to zero) decreases the extra calcium seen on a subsequent restretch. After such a shortening step, the extra calcium on stretch recovers (50 ms half time) toward the control level with the same time course as the redeveloped force. Conversely, stretching an active fiber decreases the extra calcium on a subsequent shortening step that is imposed shortly afterward. Enhanced calcium binding due to increased length alone cannot explain our data. We hypothesize that the calcium affinity of the activating sites increases with cross-bridge attachment and further with cross-bridge strain. This accounts for the biphasic response to stretch as follows: cross-bridges detached by stretch first decrease calcium affinity, then upon reattachment increase calcium affinity due to the strained configuration brought on by the stretch. The experiments suggest that cross-bridge attachment and strain can modify calcium binding to the activating sites in intact muscle.

scholarly journals Active force inhibition and stretch-induced force enhancement in frog muscle treated with BDM

2004 ◽  
Vol 97 (4) ◽  
pp. 1395-1400 ◽  
Author(s):  
Dilson E. Rassier ◽  
Walter Herzog
Keyword(s):  
Fiber Length ◽  
Isometric Force ◽  
Ringer Solution ◽  
Total Force ◽  
Passive Force ◽  
Force Enhancement ◽  
Cross Bridge ◽  
Length Relationship ◽  
Cross Bridges ◽  
Lumbrical Muscles

There is evidence that the stretch-induced residual force enhancement observed in skeletal muscles is associated with 1) cross-bridge dynamics and 2) an increase in passive force. The purpose of this study was to characterize the total and passive force enhancement and to evaluate whether these phenomena may be associated with a slow detachment of cross bridges. Single fibers from frog lumbrical muscles were placed at a length 20% longer than the plateau of the force-length relationship, and active and passive stretches (amplitudes of 5 and 10% of fiber length and at a speed of 40% fiber length/s) were performed. Experiments were conducted in Ringer solution and with the addition of 2, 5, and 10 mM of 2,3-butanedione monoxime (BDM), a cross-bridge inhibitor. The steady-state active and passive isometric forces after stretch of an activated fiber were higher than the corresponding forces measured after isometric contractions or passive stretches. BDM decreased the absolute isometric force and increased the total force enhancement in all conditions investigated. These results suggest that total force enhancement is directly associated with cross-bridge kinetics. Addition of 2 mM BDM did not change the passive force enhancement after 5 and 10% stretches. Addition of 5 and 10 mM did not change (5% stretches) or increased (10% stretches) the passive force enhancement. Increasing stretch amplitudes and increasing concentrations of BDM caused relaxation after stretch to be slower, and because passive force enhancement is increased at the greatest stretch amplitudes and the highest BDM concentrations, it appears that passive force enhancement may be related to slow-detaching cross bridges.

Effect of Vitamin D Deficiency on Sarcoplasmic Reticulum Function and Troponin C Concentration of Rabbit Skeletal Muscle

1979 ◽  
Vol 57 (3) ◽  
pp. 257-263 ◽  
Author(s):  
Jennifer J. Pointon ◽  
M. J. O. Francis ◽  
R. Smith
Keyword(s):  
Vitamin D ◽  
Sarcoplasmic Reticulum ◽  
Calcium Binding ◽  
Quadriceps Muscle ◽  
Troponin C ◽  
Muscle Physiology ◽  
Deficient Diet ◽  
Troponin Complex ◽  
Binding Component ◽  
Dietary Deficiency

1. Weanling rabbits were made rachitic either by a vitamin D-deficient diet or by parenteral administration of ethane 1-hydroxy-1,1-diphosphonate (EHDP) in amounts sufficient in other species to block the formation of 1,25-dihydroxycholecalciferol [1,25-(OH)2D,]. 2. The uptake of calcium into the isolated sarcoplasmic reticulum from mixed striated quadriceps muscle, and the amount of troponin C (the calcium-binding component of the troponin complex) in relation to other proteins from the same muscle, were measured. 3. In muscle from animals made rachitic by a dietary deficiency of vitamin D, the rate of uptake of calcium by the sarcoplasmic reticulum and the troponin C concentration were both significantly less (P < 0·02) than in control littermates. In EHDP-treated animals no significant differences from controls were found. 4. These results show that dietary deficiency of vitamin D in such animals can affect muscle physiology. Since no changes are found in animals made rachitic with EHDP, who presumably have a selective deficiency of 1,25-(OH)2D3, it is possible that the effect of vitamin D on muscle is mediated through metabolites other than 1,25-(OH)2D3 such as 25-hydroxycholecalciferol.

Myocardial cross-bridge kinetics in transition to failure in Dahl salt-sensitive rats

2001 ◽  
Vol 281 (3) ◽  
pp. H1390-H1396 ◽  
Author(s):  
Daniel T. McCurdy ◽  
Bradley M. Palmer ◽  
David W. Maughan ◽  
Martin M. LeWinter
Keyword(s):  
Mechanical Performance ◽  
Dynamic Stiffness ◽  
Calcium Sensitivity ◽  
Left Ventricular ◽  
Isometric Tension ◽  
High Salt Diet ◽  
Salt Diet ◽  
Cross Bridge ◽  
Cross Bridges

The role of altered cross-bridge kinetics during the transition from cardiac hypertrophy to failure is poorly defined. We examined this in Dahl salt-sensitive (DS) rats, which develop hypertrophy and failure when fed a high-salt diet (HS). DS rats fed a low-salt diet were controls. Serial echocardiography disclosed compensated hypertrophy at 6 wk of HS, followed by progressive dilatation and impaired function. Mechanical properties of skinned left ventricular papillary muscle strips were analyzed at 6 wk of HS and then during failure (12 wk HS) by applying small amplitude (0.125%) length perturbations over a range of calcium concentrations. No differences in isometric tension-calcium relations or cross-bridge cycling kinetics or mechanical function were found at 6 wk. In contrast, 12 wk HS strips exhibited increased calcium sensitivity of isometric tension, decreased frequency of minimal dynamic stiffness, and a decreased range of frequencies over which cross bridges produce work and power. Thus the transition from hypertrophy to heart failure in DS rats is characterized by major changes in cross-bridge cycling kinetics and mechanical performance.

Mechanical Modulation of the Ca2+ Regulatory Protein Complex in Cardiac Muscle

Physiology ◽  
1995 ◽  
Vol 10 (1) ◽  
pp. 6-12
Author(s):  
F Fuchs
Keyword(s):  
Cardiac Muscle ◽  
Protein Complex ◽  
Regulatory Protein ◽  
Cross Bridge ◽  
Length Relationship ◽  
Mechanical Modulation ◽  
Mechanical Feedback

The regulatory protein complex of cardiac myofilaments not only mediates Ca2+ activation of cross-bridge cycling but serves as a pathway through which changes in load or length can modify Ca2+ regulation. This mechanical feedback may be an important component of the steep force-length relationship in the myocardium.

Sign in / Sign up

Export Citation Format

Share Document