Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling
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{"title"=>"Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling", "type"=>"journal", "authors"=>[{"first_name"=>"Hannes", "last_name"=>"Hettling", "scopus_author_id"=>"26647591100"}, {"first_name"=>"Johannes H G M", "last_name"=>"van Beek", "scopus_author_id"=>"7005937089"}], "year"=>2011, "source"=>"PLoS Computational Biology", "identifiers"=>{"issn"=>"1553734X", "scopus"=>"2-s2.0-80052337295", "pui"=>"362471798", "doi"=>"10.1371/journal.pcbi.1002130", "sgr"=>"80052337295", "pmid"=>"21912519"}, "id"=>"ea54e787-e4e8-36ff-9b0d-aa9e2cfc3e5b", "abstract"=>"In this study the function of the two isoforms of creatine kinase (CK; EC 2.7.3.2) in myocardium is investigated. The 'phosphocreatine shuttle' hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using 'sloppy modeling' ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15+/-8% (mean+/-SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 microM*s(-1)) in myofibrils. CK inhibition by 98% in silico leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215+/-23 to 566+/-31 microM*s(-1), while amplitudes of oscillations in cytosolic ADP concentration double from 77+/-11 to 146+/-1 microM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect.", "link"=>"http://www.mendeley.com/research/analyzing-functional-properties-creatine-kinase-system-multiscale-sloppy-modeling", "reader_count"=>49, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>15, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>14, "Student > Master"=>7, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>15, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>14, "Student > Master"=>7, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Agricultural and Biological Sciences"=>24, "Philosophy"=>1, "Veterinary Science and Veterinary Medicine"=>1, "Chemistry"=>1, "Computer Science"=>2, "Engineering"=>4, "Biochemistry, Genetics and Molecular Biology"=>7, "Mathematics"=>3, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Sports and Recreations"=>1, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Psychology"=>{"Psychology"=>1}, "Mathematics"=>{"Mathematics"=>3}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Engineering"=>{"Engineering"=>4}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>24}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Philosophy"=>{"Philosophy"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "Latvia"=>1, "United States"=>2, "Brazil"=>1, "Germany"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/746465"], "description"=>"<p>(A) Forcing function of pulsatile cytosolic ATP hydrolysis for the last two cardiac cycles of a simulation over 60 s. (B) Prediction of the relative PCr contribution to high-energy phosphate flux across the mitochondrial outer membrane (R<sub>diff,PCr</sub>) at heart rate 220 bpm. The shaded region gives the central 95% confidence interval of the R<sub>diff,PCr</sub> trajectories derived from ensemble simulations of 658 parameter sets. Solid lines depict a single simulation of the best scoring parameter set. Blue color indicates the condition with CK active. Simulations with CK inhibited by 98% by IA are plotted in orange. Note that two cardiac cycles are plotted after a steady state was reached.</p>", "links"=>[], "tags"=>["mitochondria", "cytosol"], "article_id"=>416845, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g004", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Prediction_of_energy_transport_from_mitochondria_to_cytosol_by_PCr_/416845", "title"=>"Prediction of energy transport from mitochondria to cytosol by PCr.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:54:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/376289", "https://ndownloader.figshare.com/files/376315", "https://ndownloader.figshare.com/files/376328", "https://ndownloader.figshare.com/files/376391"], "description"=>"<div><p>In this study the function of the two isoforms of creatine kinase (CK; EC 2.7.3.2) in myocardium is investigated. The ‘phosphocreatine shuttle’ hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using ‘sloppy modeling’ ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15±8% (mean±SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 µM*s<sup>−1</sup>) in myofibrils. CK inhibition by 98% <em>in silico</em> leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215±23 to 566±31 µM*s<sup>−1</sup>, while amplitudes of oscillations in cytosolic ADP concentration double from 77±11 to 146±1 µM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect.</p> </div>", "links"=>[], "tags"=>["analyzing", "properties", "creatine", "kinase", "multiscale", "modeling"], "article_id"=>134334, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002130.s001", "https://dx.doi.org/10.1371/journal.pcbi.1002130.s002", "https://dx.doi.org/10.1371/journal.pcbi.1002130.s003", "https://dx.doi.org/10.1371/journal.pcbi.1002130.s004"], "stats"=>{"downloads"=>25, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Analyzing_the_Functional_Properties_of_the_Creatine_Kinase_System_with_Multiscale_Sloppy_Modeling/134334", "title"=>"Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-08-11 01:12:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/746594"], "description"=>"<p>Plots show (A–C) Trajectory of the forcing function of ATP hydrolysis and ensemble predictions of (D–F) R<sub>diff,PCr</sub>, (G–I) mitochondrial ATP synthesis rate, (J–L) cytosolic ADP and (M–O) cytosolic P<sub>i</sub> concentrations at heart rate 220 bpm. Mi-CK and MM-CK activities were set to 2, 100, and 300% of wildtype levels. Three cardiac cycles are shown at steady state. Solid lines show the simulated trajectory of the optimized parameter set (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi-1002130-t001\" target=\"_blank\">Table 1</a>). Shaded regions show the 95% confidence interval for all trajectories of the ensemble of 658 parameter sets. To alter CK activity, the parameters describing maximum enzyme velocity, V<sub>max,Mif</sub> and V<sub>max,MMf</sub>, are changed in parallel to the indicated percentage.</p>", "links"=>[], "tags"=>["metabolite", "concentrations", "fluxes", "cardiac", "levels", "ck"], "article_id"=>416967, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g006", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fluctuations_of_metabolite_concentrations_and_fluxes_during_the_cardiac_cycle_at_three_levels_of_CK_activity_/416967", "title"=>"Fluctuations of metabolite concentrations and fluxes during the cardiac cycle at three levels of CK activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:56:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/746749"], "description"=>"<p>Shown are the time courses of (A) ATP hydrolysis and (B) synthesis simulated with the model of <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi-1002130-g001\" target=\"_blank\">Figure 1</a>. At time 0 s, average ATP hydrolysis rate was increased from 486.5 to 627.6 µM*s<sup>−1</sup> corresponding to an increase in heart rate from 135 to 220 bpm, as was imposed in the experiments which were simulated in this study. Please note the difference in scale of the y-axis between panels A and B.</p>", "links"=>[], "tags"=>["beating"], "article_id"=>417128, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g008", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pulsatile_nature_of_energy_production_and_consumption_in_the_beating_heart_and_the_response_to_a_step_in_heart_rate_/417128", "title"=>"Pulsatile nature of energy production and consumption in the beating heart and the response to a step in heart rate.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:58:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/746675"], "description"=>"<p>In the first row (panels A–D), the pulsatile forcing function for ATP hydrolysis is plotted. Predictions of the time courses of (E–H) relative contribution of PCr to high-energy phosphate transport, R<sub>diff,PCr</sub>, (I–L) ATP synthesis rate, (M–P) cytosolic ADP and (Q–T) P<sub>i</sub> concentrations. Heart rate is 220 bpm. In the four columns we compare: no CK inhibition, 98% Mi-CK inhibition, 98% MM-CK, or both CK enzyme reactions inhibited by 98%. Black solid lines show the simulated trajectory of the optimized parameter set (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi-1002130-t001\" target=\"_blank\">Table 1</a>). Blue shaded regions show the 95% central confidence interval for all trajectories of the ensemble of 658 parameter sets. To alter CK activity, the parameters describing maximum enzyme velocity, V<sub>max,Mif</sub> and V<sub>max,MMf</sub>, are changed to the indicated percentage. Three cardiac cycles are shown after a steady state was reached. Note that the first and the last column also appear in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi-1002130-g006\" target=\"_blank\">Figure 6</a> and are shown here for ease of comparison.</p>", "links"=>[], "tags"=>["predictions", "metabolite", "flux", "oscillations", "cardiac", "selective", "ck", "isoform"], "article_id"=>417045, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g007", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ensemble_predictions_of_metabolite_concentration_and_flux_oscillations_during_the_cardiac_cycle_for_selective_CK_isoform_inhibition_/417045", "title"=>"Ensemble predictions of metabolite concentration and flux oscillations during the cardiac cycle for selective CK isoform inhibition.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:57:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/746283"], "description"=>"<p>The response times of oxidative phosphorylation (t<sub>mito</sub>) were measured in isolated rabbit hearts <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi.1002130-Harrison2\" target=\"_blank\">[9]</a>. Model parameters were estimated using a modified Levenberg-Marquardt algorithm. Red bars represent the t<sub>mito</sub> values from the experiment, yellow bars represent the t<sub>mito</sub> values predicted by the model after the fitting procedure. Data is available for six different conditions: three different amplitudes of heart rate jump (from 135 bpm to 160, 190 and 220 bpm heart rate), each one measured with full wildtype CK activity (100%) or with CK activity inhibited to 2% of wildtype value. The error bars reflect the standard error of the measurements and the standard deviation of the t<sub>mito</sub> values in the ensemble, respectively.</p>", "links"=>[], "tags"=>["times"], "article_id"=>416670, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g002", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fit_by_the_model_of_measured_response_times_to_heart_rate_steps_/416670", "title"=>"Fit by the model of measured response times to heart rate steps.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:51:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/746390"], "description"=>"<p>Plots show histograms of all values in the ensemble for the given parameter. The ensemble consists of 658 parameter sets. Plotted in red is the probability density function of the lognormal distribution with mean and standard deviation of each parameter scaled to the observed frequencies.</p>", "links"=>[], "tags"=>["parameters", "ensemble", "generated", "metropolis-hastings"], "article_id"=>416769, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distributions_of_individual_parameters_in_the_ensemble_generated_by_the_Metropolis_Hastings_algorithm_/416769", "title"=>"Distributions of individual parameters in the ensemble generated by the Metropolis-Hastings algorithm.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:52:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/746232"], "description"=>"<p>Main elements are ATP hydrolysis by ATPase, ATP synthesis by mitochondria and creatine kinase (CK) isoforms in the mitochondrial intermembrane space (Mi-CK) and cytosol (MM-CK). Oxidative phosphorylation (OxPhos) takes place in the mitochondrial matrix and responds to ADP and inorganic phosphate (P<sub>i</sub>) levels in the mitochondrial intermembrane space. The concentrations of phosphocreatine (PCr), creatine (Cr), ADP, ATP and P<sub>i</sub> are dependent on the rates of the enzyme reactions and transport. The figure was generated with CellDesigner <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi.1002130-Funahashi1\" target=\"_blank\">[57]</a>.</p>", "links"=>[], "tags"=>["compartmentalized", "creatine", "kinase"], "article_id"=>416606, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g001", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Scheme_of_model_of_the_compartmentalized_creatine_kinase_system_/416606", "title"=>"Scheme of model of the compartmentalized creatine kinase system.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:50:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/746801"], "description"=>"<p>Shown are all model parameters describing the enzyme kinetics and transport across the mitochondrial outer membrane. The thirds column gives the parameter values obtained from the literature. If a standard measurement error could be obtained from literature, the value is given. We also give the parameter values after least-squares optimization to experiment data. We finally give means and standard deviations of the parameter ensemble. Note that the model parameters for maximum backwards velocity of both CK reactions, V<sub>max,Mi,b</sub> and V<sub>max,MM,b</sub> are not listed because their values are dynamically calculated from other parameter values via the Haldane relation: </p>a<p>values which determine the spread of the prior distribution for parameters with standard errors not available from the experimental literature were set to 0.336, which is the maximum value for parameters where the standard error is known from the literature.</p>", "links"=>[], "tags"=>["ck"], "article_id"=>417175, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.t001", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Parameters_of_the_CK_model_/417175", "title"=>"Parameters of the CK model.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-08-11 01:59:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/746524"], "description"=>"<p>Prediction of the PCr contribution to high-energy phosphate flux across the mitochondrial outer membrane (R<sub>diff,PCr</sub>), averaged over the cardiac cycle, as a function of (A) heart rate and (B) mitochondrial outer membrane permeability for adenine nucleotides (PS<sub>mom,AdN</sub>), respectively. Values for (A) Steady state values for R<sub>diff,PCr</sub> as a function of heart rate (B) Steady state values for R<sub>diff,PCr</sub> as a function of PS<sub>mom,AdN</sub> at fixed heart rate of 220 bpm. We performed simulations for the ensemble of <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi-1002130-g003\" target=\"_blank\">Figure 3</a>, with the heart rate or PS<sub>mom,AdN</sub> set according to the x-axis. Blue shaded regions depict the 95% confidence interval of the prediction, black solid lines show the prediction for the optimized parameters (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002130#pcbi-1002130-t001\" target=\"_blank\">Table 1</a>).</p>", "links"=>[], "tags"=>["pcr", "diffusion", "flux", "mitochondrial", "membrane", "permeability", "adenine"], "article_id"=>416897, "categories"=>["Information And Computing Sciences", "Biological Sciences", "Genetics"], "users"=>["Hannes Hettling", "Johannes HGM van Beek"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002130.g005", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dependence_of_PCr_diffusion_flux_on_heart_rate_and_mitochondrial_membrane_permeability_to_adenine_nucleotides_/416897", "title"=>"Dependence of PCr diffusion flux on heart rate and mitochondrial membrane permeability to adenine nucleotides.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-11 01:54:57"}

PMC Usage Stats | Further Information

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Relative Metric

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