Evidence for a force-dependent component of calcium binding to cardiac troponin C

Hofmann, Polly A.; Fuchs, Franklin

doi:10.1152/ajpcell.1987.253.4.c541

Cited by 121 publications

(79 citation statements)

References 21 publications

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“…We can currently only speculate as to which singular determinant governs the kinetic balance between contraction and relaxation. It has been postulated that the prolongation of relaxation is governed by the feedback of cross-bridges (10) on either the detachment rate or on thin filament activation (20). This would imply that when force increases, the kinetics slow down, and a close correlation between force and kinetics would exist.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere

Janssen

2010

American Journal of Physiology-Heart and Circulatory Physiology

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Janssen PM. Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere. Am J Physiol Heart Circ Physiol 299: H1092-H1099, 2010. First published July 23, 2010; doi:10.1152/ajpheart.00417.2010.-The regulation of myocardial contraction and relaxation kinetics is currently incompletely understood. When the amplitude of contraction is increased via the Frank-Starling mechanism, the kinetics of the contraction slow down, but when the amplitude of contraction is increased with either an increase in heart rate or via ␤-adrenergic stimulation, the kinetics speed up. It is also unknown how physiological mechanisms affect the kinetics of contraction versus those of relaxation. We investigated contraction-relaxation coupling in isolated trabeculae from the mouse and rat and stimulated them to contract at various temperatures, frequencies, preloads, and in the absence and presence of ␤-adrenergic stimulation. In each muscle at least 16 different conditions were assessed, and the correlation coefficient of the speed of contraction and relaxation was very close (generally Ͼ0.98). Moreover, in all but one of the analyzed murine strains, the ratio of the minimum rate of the derivative of force development (dF/dt) over maximum dF/dt was not significantly different. Only in trabeculae isolated from myosin-binding protein-C mutant mice was this ratio significantly lower (0.61 Ϯ 0.07 vs. 0.84 Ϯ 0.02 in 11 other strains of mice). Within each strain, this ratio was unaffected by modulation of length, frequency, or ␤-adrenergic stimulation. Rat trabeculae showed identical results; the balance between kinetics of contraction and relaxation was generally constant (0.85 Ϯ 0.04). Because of the great variety in underlying excitation-contraction coupling in the assessed strains, we concluded that contraction-relation coupling is a property residing in the cardiac sarcomere. trabeculae; mouse; rat; calcium handling; exitation-contraction coupling NOT ONLY IS THE FORCEFULNESS of contraction of the myocardium important, but the speed at which the contraction and relaxation takes place is a critical determinant of cardiac performance. When the heart cannot relax sufficiently fast, and as a result cannot adequately fill the ventricles before the next excitation stimulus, cardiac output is compromised. Whether called heart failure with preserved ejection fraction, diastolic dysfunction, or impaired myocardial relaxation, inadequate relaxation kinetics of the heart pose a clinical problem that affects a very large fraction of patients with cardiac pathology (5, 16). To treat, manage, or possibly cure impaired myocardial relaxation kinetics, a better understanding of the cardiac relaxation process at the level of the cardiac muscle is warranted. It has become increasingly clear that myocardial relaxation is not a mere passive process that follows a contraction but a complex systems biology property that is brought about by a multitude of factors (30). These factors include cytosolic Ca 2ϩ ...

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Section: Discussionmentioning

confidence: 99%

Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere

Janssen

2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…This hypothesis has been tested in detail in the elegant studies of Fuchs et al 18,19,26,27 . Hofmann and Fuchs 18 measured TnC/Ca 2+ association in membrane-free cardiac fibers using isotopes, as previously explained.…”

Section: Relative Force Activation Of Cardiac Muscle and Muscle Lengtmentioning

confidence: 99%

“…The hypothesis that is being successfully tested is that the association of cross bridges of myosin with actin and consequent force generation is responsible for the dependence of the degree of activation on muscle length 18,19,[25][26][27][28][29] . The work and justification related to this hypothesis are presented below.…”

Section: Relative Force Activation Of Cardiac Muscle and Muscle Lengtmentioning

confidence: 99%

The degree of activation of cardiac muscle depends on muscle length

Rassier¹

2000

Arq. Bras. Cardiol.

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The Frank-Starling mechanism of the heart 1-3 can be described as the relationship between force and length of cardiac muscle. With the advent of the cross bridge theory of muscle contraction 4,5 and Gordon and collaborator's classical study 6 describing the fitting of this theory to the force-length relationship in skeletal muscle, several investigators started to study this relationship in cardiac muscle.The force-length relation in cardiac muscle is observed in a small variety of sarcomere lengths, between approximately 1.8 µm and 2.3 µm. This region corresponds to the ascending limb of the force-length relation of skeletal-muscle 6 . The force levels of the myocardium vary from zero at 1.8 µm to maximal force values at 2.3 µm. This large variation in force results in a very sleep force-length relation, especially when compared with this relation in skeletal muscle ( fig. 1). To get an idea, when the tension developed by the myocardium at different sarcomere lengths is normalized in relation to its maximal force (F max ) at the point where maximal length (L max ) occurs, the developed tension is approximately 10-15% when the myocardium is measured at 80% L max . Yet in skeletal muscle, normalized force is approximately 80-85% of F max 7 under the same conditions ( fig.1).This difference between skeletal and cardiac muscle shows that the force-length relationship in the myocardium are not a simple function of the degree of superposition of actin and myosin filaments. Because their lengths are similar in both muscles, other factors must be involved in the muscle force-length relationship. During recent years, this difference has been attributed to the dependence of muscle activation on sarcomere length 8 .Muscle activation has been used collectively in the literature to refer to various processes able to initiate muscle contraction, modifying the muscle state from "inactive" to "active". Thus, muscle activation has been associated with the frequency of muscle stimulation or membrane action potentials with intracellular Ca 2+ concentration [Ca 2+ ] i , or the occupation of the protein troponin C (TnC) by Ca 2+ . In this article, the term muscle contraction will be utilized to describe the proportion of TnC associated with Ca 2+ . The association TnC/Ca 2+ represents a fundamental event in muscle contraction; therefore, the sensitivity of TnC to Ca 2+ will be discussed in greater detail. This choice, furthermore, comes from studies shewing that myocardial force changes due to muscle length are unrelated to [Ca 2+ ] i 9,10 . The present article contains a review of studies related to the dependence of force and, more importantly, of the process of myocardial muscle activation on muscle length. In particular, the article intends to investigate mechanisms responsible for the dependence of the sensitivity of filaments to Ca 2+ on muscle length, as proposed in the literature.Dependence of the sensitivity of filaments to Ca 2+ on muscle length -Evidence that the activation of the myocardium is dependent on muscle lengt...

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“…k off(TnC⅐Ca) therefore becomes smaller as cross-bridges form and force develops (34,37,38). The exponential dependence of k off(TnC⅐Ca) on force is based on experimental observations in cardiac and skeletal muscle (32)(33)(34) and is quantified by the equation k off.TnC⅐Ca ϭ k off.TnC⅐Ca.rest ϫ e Ϫgain ϫ relative force , where k off.TnC⅐Ca.rest is the off-rate of Ca 2ϩ from TnC in the absence of force development.…”

Section: Force Dependence Of Affinity Of Tnc For Ca 2ϩmentioning

confidence: 99%

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

Lang¹,

Gomes²,

Zhao³

et al. 2002

Journal of Biological Chemistry

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Familial hypertrophic cardiomyopathy has been associated with several mutations in the gene encoding human cardiac troponin I (HCTnI). A missense mutation in the inhibitory region of TnI replaces an arginine residue at position 145 with a glycine and cosegregates with the disease. Results from several assays indicate that the inhibitory function of HCTnI R145G is significantly reduced. When HCTnI R145G was incorporated into whole troponin, Tn R145G (HCTnT⅐HCTnI R145G ⅐HCTnC), only partial inhibition of the actin-tropomyosin-myosin ATPase activity was observed in the absence of Ca 2؉ compared with wild type Tn (HCTnT⅐HCTnI⅐HCTnC). Maximal activation of actin-tropomyosin-myosin ATPase in the presence of Ca 2؉ was also decreased in Tn R145G when compared with Tn. Using skinned cardiac muscle fibers, we determined that in comparison with the wild type complex 1) the complex containing HCTnI R145G only inhibited 84% of Ca 2؉ -unregulated force, 2) the recovery of Ca 2؉ -activated force was decreased, and 3) there was a significant increase in the Ca 2؉ sensitivity of force development. Computer modeling of troponin C and I variables predicts that the primary defect in TnI caused by these mutations would lead to diastolic dysfunction. These results suggest that severe diastolic dysfunction and somewhat decreased contractility would be prominent clinical features and that hypertrophy could arise as a compensatory mechanism. Familial hypertrophic cardiomyopathy (FHC)1 has been linked to mutations in genes of nine different sarcomeric proteins. These mutations have been found in the genes for ␣-myosin heavy chain (1), cardiac myosin essential light chain and cardiac myosin regulatory light chain (2), ␣-tropomyosin, cardiac troponin T (TnT) (3), cardiac myosin-binding protein C (4, 5), troponin I (TnI) (6), ␣-actin (7), as well as titin (8), and possibly troponin C (TnC) (9). This disease has recently gained significant attention due to several highly publicized reports of sudden death and fainting spells in young athletes who were asymptomatic and otherwise healthy individuals. In general, patients with FHC demonstrate an increase in heart muscle mass and sometimes an irregular echocardiogram (10). Kimura et al. (6) reported five missense mutations in TnI, R145G, R145Q, R162W, G203S, and K206Q, that cosegregate with FHC (Fig. 1). Three other TnI FHC mutants (S199N, Lys-183 deletion, and an exon 8 deletion mutant encompassing the stop codon of the cardiac TnI gene) have recently been discovered (11, 12). Functionally TnI is the inhibitory subunit of the troponin (Tn) complex that controls the interaction between actin and myosin in a Ca 2ϩ -dependent manner (13-15). Studies using proteolytic fragments of fast skeletal TnI identified the central TnI sequence (residues 96 -116) as being responsible for its inhibitory activity. Residues 104 -115 of fast skeletal TnI (comparable to residues 136 -147 in cardiac TnI) formed the minimum sequence necessary for inhibition of muscle contraction (16 -19). Two of these mutations occ...

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Evidence for a force-dependent component of calcium binding to cardiac troponin C

Cited by 121 publications

References 21 publications

Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere

Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere

The degree of activation of cardiac muscle depends on muscle length

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

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