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  • Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling.
  • Hettling H, van Beek JH
  • PLoS computational biology , 8/ 2011 , Volume 7 , pages: e1002130 , PubMed ID: 21912519
  • Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam, The Netherlands.
  • In this study the function of the two isoforms of creatine kinase (CK; EC 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(-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 µM*s(-1), 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.
Hannes Hettling

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BIOMD0000000408.xml.origin SBML L2V4 representation of Hettling2011_CreatineKinase 87.21 KB Preview | Download

  • Model originally submitted by : Hannes Hettling
  • Submitted: Jan 25, 2012 12:19:15 PM
  • Last Modified: Feb 25, 2015 12:27:50 PM
  • Version: 2 public model Download this version
    • Submitted on: Feb 25, 2015 12:27:50 PM
    • Submitted by: Hannes Hettling
    • With comment: Current version of Hettling2011_CreatineKinase
  • Version: 1 public model Download this version
    • Submitted on: Jan 25, 2012 12:19:15 PM
    • Submitted by: Hannes Hettling
    • With comment: Original import of Hettling_VanBeek_creatine_kinase_2011

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Curator's comment:
(added: 26 Jan 2012, 13:59:29, updated: 26 Jan 2012, 13:59:29)
Figure 8 of the reference publication has been reproduced using Copasi v4.7 (Build 34)