PMID- 18375588
OWN - NLM
STAT- MEDLINE
DCOM- 20080811
LR  - 20131121
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 1123
DP  - 2008 Mar
TI  - Multiscale and modular analysis of cardiac energy metabolism: repairing the 
      broken interfaces of isolated system components.
PG  - 155-68
LID - 10.1196/annals.1420.018 [doi]
AB  - Computational models of large molecular systems can be assembled from modules 
      representing biological function emerging from interactions among a small subset 
      of molecules. Experimental information on isolated molecules can be integrated 
      with the response of the network as a whole to estimate crucial missing 
      parameters. As an example, a "skeleton" model is analyzed for the module 
      regulating dynamic adaptation of myocardial oxidative phosphorylation (OxPhos) to 
      fluctuating cardiac energy demand. The module contains adenine nucleotides, 
      creatine, and phosphate groups. Enzyme kinetic equations for two creatine kinase 
      (CK) isoforms were combined with the response time of OxPhos (t mito; generalized 
      time constant) to steps in the cardiac pacing rate to identify all module 
      parameters. To obtain t mito, the time course of O2 uptake was measured for the 
      whole heart. An O2 transport model was used to deconvolute the whole-heart 
      response to the mitochondrial level. By optimizing mitochondrial outer membrane 
      permeability to 21 microm/s the experimental t mito = 3.7 s was reproduced. This 
      in vivo value is about four times larger, or smaller, respectively, than 
      conflicting values obtained from two different in vitro studies. This 
      demonstrates an important rule for multiscale analysis: experimental responses 
      and modeling of the system at the larger scale allow one to estimate essential 
      parameters for the interfaces of components which may have been altered during 
      physical isolation. The model correctly predicts a smaller t mito when CK 
      activity is reduced. The model further predicts a slower response if the muscle 
      CK isoform is overexpressed and a faster response if mitochondrial CK is 
      overexpressed. The CK system is very effective in decreasing maximum levels of 
      ADP during systole and reducing average Pi levels over the whole cardiac cycle.
FAU - Van Beek, Johannes H G M
AU  - Van Beek JH
AD  - Centre for Intergrative BioInformatics, VU University, Amsterdam, the 
      Netherlands. hans.van.beek@falw.vu.nl
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (Nucleotides)
RN  - EC 2.7.3.2 (Creatine Kinase)
RN  - MU72812GK0 (Creatine)
SB  - IM
MH  - Animals
MH  - Creatine/metabolism
MH  - Creatine Kinase/metabolism
MH  - *Energy Metabolism
MH  - Intracellular Membranes/metabolism
MH  - Kinetics
MH  - Mitochondria, Heart/metabolism
MH  - *Models, Cardiovascular
MH  - Models, Theoretical
MH  - Myocardium/*metabolism
MH  - Nucleotides/metabolism
MH  - Oxidative Phosphorylation
MH  - Reproducibility of Results
EDAT- 2008/04/01 09:00
MHDA- 2008/08/12 09:00
CRDT- 2008/04/01 09:00
PHST- 2008/04/01 09:00 [pubmed]
PHST- 2008/08/12 09:00 [medline]
PHST- 2008/04/01 09:00 [entrez]
AID - 1123/1/155 [pii]
AID - 10.1196/annals.1420.018 [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2008 Mar;1123:155-68. doi: 10.1196/annals.1420.018.