The Rates of Ca2+ Dissociation and Cross-bridge Detachment from Ventricular Myofibrils as Reported by a Fluorescent Cardiac Troponin C

Little, Sean C.; Biesiadecki, Brandon J.; Kilic, Ahmet; Higgins, Robert S.D.; Janssen, Paul M. L.; Davis, Jonathan P.

doi:10.1074/jbc.m111.337295

Cited by 40 publications

(61 citation statements)

References 65 publications

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“…Historically, the rate of cross-bridge detachment was thought to be rate limiting because it was significantly slower than the rate of Ca 2ϩ dissociation from TnC (11,23). However, newer data suggest that the rate of cross-bridge detachment is temperature sensitive, and, at near physiological temperatures, the rate of cross-bridge detachment is faster than the rate of Ca 2ϩ dissociation from TnC, suggesting that Ca 2ϩ is rate limiting (23). Several thick and thin myofilament proteins have been shown to alter cross-bridge cycling kinetics as well as myofilament Ca 2ϩ sensitivity, and, as mentioned, we have demonstrated changes in these proteins in our model.…”

Section: Discussionmentioning

confidence: 99%

“…cMyBP-C regulates thick-filament function, and phosphorylation at Ser-273, Ser-282, and Ser-302 appears to accelerate cross-bridge cycling, increasing force development as well as relaxation (9,33). cTnI regulates thin-filament function, and Ser-23/24 phosphorylation by PKA decreases Ca 2ϩ sensitivity and myofilament cross-bridge cycling kinetics (31,36) and increases the rate of cTnC-Ca 2ϩ dissociation (23). Finally, chemically skinned myocardium containing primarily ␣-MHC has a higher ATPase rate, faster sarcomeric shortening velocity, faster rate of tension relaxation, higher power production, and greater rate of force development compared with ␤-MHC (11,39).…”

Section: Discussionmentioning

confidence: 99%

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Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

Wilson

Guggilam

West

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Wilson K, Guggilam A, West TA, Zhang X, Trask AJ, Cismowski MJ, de Tombe P, Sadayappan S, Lucchesi PA. Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure. Am J Physiol Heart Circ Physiol 307: H1605-H1617, 2014. First published September 26, 2014 doi:10.1152/ajpheart.00423.2014.-Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 wk post-ACF; REV) results in rapid structural but delayed functional recovery. This study investigated myocyte and myofilament function in ACF and REV and tested the hypothesis that a myofilament Ca 2ϩ sensitizer would improve VOinduced myofilament dysfunction in ACF and REV. Following the initial sham or ACF surgery in male Sprague-Dawley rats (200 -240 g) at week 0, REV surgery and experiments were performed at weeks 4 and 8, respectively. In ACF, decreased LV function is accompanied by impaired sarcomeric shortening and force generation and decreased Ca 2ϩ sensitivity, whereas, in REV, impaired LV function is accompanied by decreased Ca 2ϩ sensitivity. Intravenous levosimendan (Levo) elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (water) or Levo (1 mg/kg) in drinking water from weeks 4 -8. Levo improved systolic (% fractional shortening, end-systolic elastance, and preload-recruitable stroke work) and diastolic (, dP/ dt min) function in ACF and REV. Levo improved Ca 2ϩ sensitivity without altering the amplitude and kinetics of the intracellular Ca 2ϩ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cardiac troponin I Ser-23/24 phosphorylation correlated with improved diastolic relaxation, whereas, in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased ␣-to-␤-myosin heavy chain correlated with improved diastolic relaxation. We concluded that Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function. myofilament dysfunction; myofilament Ca 2ϩ sensitization; levosimendan; myosin-binding protein-C; troponin I MITRAL REGURGITATION (MR) is the most and second most common valve lesion in the United States and Europe, respectively, affecting Ͼ2 million Americans (10, 16). The pathophysiological consequences of MR include chronic left ventricular (LV) hemodynamic volume overload (VO) followed by LV chamber dilation, progressive LV contractile dysfunction, and heart failure (HF). Despite the clinical importance of VO, few models mimic the pathophysiological progression of chronic VO with and without hemodynamic load reduction. The aortocaval fistula (ACF) model of VO HF in the rodent mimics increased hemodynamic preload observed in human disease, irrespective of etiology. In this model, chronically increased LV preload leads to progressive LV pump failure, which is classified into t...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

Wilson

Guggilam

West

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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show abstract

“…With respect to troponin, our new active contraction model inherits troponin C dynamics and parameters other than calcium sensitivity from previous murine work [37], as these proteins are highly conserved across species [41], and we do not have new experimental data to constrain most of the parameters:…”

Section: Thin Filament Kineticsmentioning

confidence: 99%

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

Land

Park-Holohan

Smith

et al. 2017

Journal of Molecular and Cellular Cardiology

114

147

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Experimental data from human cardiac myocytes at body temperature is crucial for a quantitative understanding of clinically relevant cardiac function and development of whole-organ computational models. However, such experimental data is currently very limited. Specifically, important measurements to characterize changes in tension development in human cardiomyocytes that occur with perturbations in cell length are not available. To address this deficiency, in this study we present an experimental data set collected from skinned human cardiac myocytes, including the passive and viscoelastic properties of isolated myocytes, the steady-state force calcium relationship at different sarcomere lengths, and changes in tension following a rapid increase or decrease in length, and after constant velocity shortening. This data set is, to our knowledge, the first characterization of length and velocity-dependence of tension generation in human skinned cardiac myocytes at body temperature.We use this data to develop a computational model of contraction and passive viscoelasticity in human myocytes. Our model includes troponin C kinetics, tropomyosin kinetics, a three-state crossbridge model that accounts for the distortion of crossbridges, and the cellular viscoelastic response. Each component is parametrized using our experimental data collected in human cardiomyocytes at body temperature. Furthermore we are able to confirm that properties of length-dependent activation at 37• C are similar to other species, with a shift in calcium sensitivity and increase in maximum tension. We revise our model of tension generation in the skinned isolated myocyte to replicate reported tension traces generated in intact muscle during isometric tension, to provide a model of human tension generation for multi-scale simulations. This process requires changes to calcium sensitivity, cooperativity, and crossbridge transition rates. We apply this model within multi-scale simulations of biventricular cardiac function and further refine the parametrization within the whole organ context, based on obtaining a healthy ejection fraction. This process reveals that crossbridge cycling rates differ between skinned myocytes and intact myocytes.

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“…TnI and Tm are key players in the thinfilament response and either protein can dominate the relaxation rate, depending on experimental conditions and the specific mutations involved (35,62).…”

Section: Rate Of Myofibrillar Relaxationmentioning

confidence: 99%

S-Nitrosylation of Sarcomeric Proteins Depresses Myofilament Ca²⁺ Sensitivity in Intact Cardiomyocytes

Figueiredo-Freitas

Dulce

Foster

et al. 2015

Antioxidants & Redox Signaling

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Aims: The heart responds to physiological and pathophysiological stress factors by increasing its production of nitric oxide (NO), which reacts with intracellular glutathione to form S-nitrosoglutathione (GSNO), a protein S-nitrosylating agent. Although S-nitrosylation protects some cardiac proteins against oxidative stress, direct effects on myofilament performance are unknown. We hypothesize that S-nitrosylation of sarcomeric proteins will modulate the performance of cardiac myofilaments. Results: Incubation of intact mouse cardiomyocytes with S-nitrosocysteine (CysNO, a cell-permeable low-molecular-weight nitrosothiol) significantly decreased myofilament Ca 2+ sensitivity. In demembranated (skinned) fibers, S-nitrosylation with 1 lM GSNO also decreased Ca 2+ sensitivity of contraction and 10 lM reduced maximal isometric force, while inhibition of relaxation and myofibrillar ATPase required higher concentrations ( ‡100 lM). Reducing S-nitrosylation with ascorbate partially reversed the effects on Ca 2+ sensitivity and ATPase activity. In live cardiomyocytes treated with CysNO, resin-assisted capture of S-nitrosylated protein thiols was combined with label-free liquid chromatography-tandem mass spectrometry to quantify S-nitrosylation and determine the susceptible cysteine sites on myosin, actin, myosin-binding protein C, troponin C and I, tropomyosin, and titin. The ability of sarcomere proteins to form S-NO from 10-500 lM CysNO in intact cardiomyocytes was further determined by immunoblot, with actin, myosin, myosin-binding protein C, and troponin C being the more susceptible sarcomeric proteins. Innovation and Conclusions: Thus, specific physiological effects are associated with S-nitrosylation of a limited number of cysteine residues in sarcomeric proteins, which also offer potential targets for interventions in pathophysiological situations.

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The Rates of Ca2+ Dissociation and Cross-bridge Detachment from Ventricular Myofibrils as Reported by a Fluorescent Cardiac Troponin C

Cited by 40 publications

References 65 publications

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

S-Nitrosylation of Sarcomeric Proteins Depresses Myofilament Ca²⁺ Sensitivity in Intact Cardiomyocytes

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The Rates of Ca2+ Dissociation and Cross-bridge Detachment from Ventricular Myofibrils as Reported by a Fluorescent Cardiac Troponin C

Cited by 40 publications

References 65 publications

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

S-Nitrosylation of Sarcomeric Proteins Depresses Myofilament Ca2+ Sensitivity in Intact Cardiomyocytes

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Product

Resources

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S-Nitrosylation of Sarcomeric Proteins Depresses Myofilament Ca²⁺ Sensitivity in Intact Cardiomyocytes