Insights into the kinetics of Ca2+-regulated contraction and relaxation from myofibril studies

Stehle, Robert; Solzin, Johannes; Iorga, Bogdan; Poggesi, Corrado

doi:10.1007/s00424-008-0630-2

Cited by 68 publications

(81 citation statements)

References 155 publications

(387 reference statements)

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“…In addition, following Ca 2ϩ activation when steady-state activation was reached, a rapid release-restretch maneuver was imposed to measure k tr , an index that is proportional to the sum of the apparent cross-bridge attachment and detachment rates (30,31). The rates of Ca 2ϩ activation (k Ca ) and k tr were similar in the present study in all experimental groups, consistent with previous reports (29). This finding indicates that the dynamics of Ca 2ϩ binding to cTnI and the subsequent thin filament activation are sufficiently fast to not be rate-limiting for force development.…”

Section: Impact Of Isolated Pka/pkc/rcm On Myofilament Casupporting

confidence: 79%

“…Single Myofibril Activation/Relaxation Kinetics-The single myofibril technique allows for measurement of dynamic Ca 2ϩ activation/relaxation kinetics of force (27)(28)(29). In addition, following Ca 2ϩ activation when steady-state activation was reached, a rapid release-restretch maneuver was imposed to measure k tr , an index that is proportional to the sum of the apparent cross-bridge attachment and detachment rates (30,31).…”

Section: Impact Of Isolated Pka/pkc/rcm On Myofilament Camentioning

confidence: 99%

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Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres

Dvornikov

Smolin

Zhang

et al. 2016

Journal of Biological Chemistry

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The cardiac troponin I (cTnI) R145W mutation is associated with restrictive cardiomyopathy (RCM). Recent evidence suggests that this mutation induces perturbed myofilament lengthdependent activation (LDA) under conditions of maximal protein kinase A (PKA) stimulation. Some cardiac disease-causing mutations, however, have been associated with a blunted response to PKA-mediated phosphorylation; whether this includes LDA is unknown. Endogenous troponin was exchanged in isolated skinned human myocardium for recombinant troponin containing either cTnI R145W, PKA/PKC phosphomimetic charge mutations (S23D/S24D and T143E), or various combinations thereof. Myofilament Ca 2؉ sensitivity of force, tension cost, LDA, and single myofibril activation/relaxation parameters were measured. Our results show that both R145W and T143E uncouple the impact of S23D/S24D phosphomimetic on myofilament function, including LDA. Molecular dynamics simulations revealed a marked reduction in interactions between helix C of cTnC (residues 56, 59, and 63), and cTnI (residue 145) in the presence of either cTnI RCM mutation or cTnI PKC phosphomimetic. These results suggest that the RCM-associated cTnI R145W mutation induces a permanent structural state that is similar to, but more extensive than, that induced by PKC-mediated phosphorylation of cTnI Thr-143. We suggest that this structural conformational change induces an increase in myofilament Ca 2؉ sensitivity and, moreover, uncoupling from the impact of phosphorylation of cTnI mediated by PKA at the Ser-23/Ser-24 target sites. The R145W RCM mutation by itself, however, does not impact LDA. These perturbed biophysical and biochemical myofilament properties are likely to significantly contribute to the diastolic cardiac pump dysfunction that is seen in patients suffering from a restrictive cardiomyopathy that is associated with the cTnI R145W mutation.Cardiomyopathies are diseases of the heart muscle that are either acquired or inherited (1). Several forms of the disease are formally recognized, including dilated cardiomyopathy, hypertrophic cardiomyopathy (HCM), 2 and restrictive cardiomyopathy (RCM) cardiomyopathy. Numerous mutations in sarcomeric proteins have been identified that associate with, and may indeed be causal to, inherited cardiomyopathy, notably the giant elastic protein titin (TTN) in dilated cardiomyopathy (2) and myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3) in HCM (3). RCM is a rare form of cardiomyopathy characterized by severe diastolic dysfunction secondary to significant increased ventricular diastolic stiffness but without the prominent increase in wall thickness that is commonly seen in HCM (4). RCM is associated with a poor prognosis (1), and the inherited form is believed to be caused by mutations in various sarcomeric proteins, including cardiac troponin I (TNNI3) (5).Troponin-I (TnI) is the inhibitory component of troponin, the trimeric thin filament-associated protein complex that mediates calcium-initiated contraction in striated muscle (see Fig...

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Section: Impact Of Isolated Pka/pkc/rcm On Myofilament Casupporting

confidence: 79%

Section: Impact Of Isolated Pka/pkc/rcm On Myofilament Camentioning

confidence: 99%

Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres

Dvornikov

Smolin

Zhang

et al. 2016

Journal of Biological Chemistry

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“…R-t EMG-F, the mainly electrochemical component of R-Delay TOT , likely includes the beginning of Ca 2+ reuptake in the sarcoplasmic reticulum and the transition of cross-bridges from a forcegenerating to a non-force-generating status [17,18,40,41]. The previously mentioned alteration in chloride channels excitability and in SERCA1 and CACNA1S splicing, may have delayed Ca 2+ reuptake in the sarcoplasmic reticulum, [11], and in turn lengthened the mainly electrochemical RDelay TOT component.…”

Section: Delays During Muscle Relaxationmentioning

confidence: 98%

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

Esposito

Cè

Rampichini

et al. 2016

Neuromuscular Disorders

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights Patients with myotonic dystrophy type 1 (DM1) were investigated isometrically  We calculated the electromechanical delays during muscle contraction and relaxation  Delays were partitioned into electrochemical and mechanical components  Measurements reliability was very high in both patients and controls  Delays were longer in DM1, especially during muscle relaxation AbstractThe electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Components duration and measurements reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n=13) and in healthy controls (n=13). EMG, mechanomyogram, and force were recorded in DM1 and in age-and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically-evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles.Measurements reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions.

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“…Both the passive tension of titin and the active tension of cross-bridges can elevate sarcomere tension during relaxation and thus impair ventricular filling. Incomplete inactivation, either due to an incomplete reduction in [Ca 2+ ] to fully relaxing concentrations or due to an incomplete switching off of the regulatory troponin-tropomyosin system, causes residual active tension and slows relaxation (Iorga et al, 2008;Kruger et al, 2005;Stehle et al, 2009). Here, we use the N2B-knockout mice as a genetic model of diastolic dysfunction to investigate whether increased titin-based stiffness also slows down cardiac myofibrillar relaxation.…”

Section: Introductionmentioning

confidence: 99%

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Elhamine

Radkë

Pfitzer

et al. 2014

Journal of Cell Science

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Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca 2+ -induced force development (rate constant k ACT ), myofibrils from knockout, heterozygous and wildtype mice were stretched to the same sarcomere length (2.3 mm) and rapidly activated with Ca 2+. Additionally, mechanically induced force-redevelopment kinetics (rate constant k TR ) were determined by slackening and re-stretching myofibrils during Ca 2+ -mediated activation. Myofibrils from knockout mice exhibited significantly higher k ACT , k TR and maximum Ca 2+ -activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca 2+ ] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating crossbridges without decelerating relaxation.

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Insights into the kinetics of Ca2+-regulated contraction and relaxation from myofibril studies

Cited by 68 publications

References 155 publications

Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres

Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

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