Abstract
There has been much debate on the mechanism of regulation
of mitochondrial ATP synthesis to balance ATP consumption
during changing cardiac workloads. A key role of
creatine kinase (CK) isoenzymes in this regulation of oxidative
phosphorylation and in intracellular energy transport
had been proposed, but has in the mean time been disputed
for many years. It was hypothesized that high-energy phosphoryl
groups are obligatorily transferred via CK; this is
termed the phosphocreatine shuttle. The other important
role ascribed to the CK system is its ability to bu er ADP
concentration in cytosol near sites of ATP hydrolysis.
Almost all of the experiments to determine the role of CK
had been done in the steady state, but recently the dynamic
response of oxidative phosphorylation to quick changes in
cytosolic ATP hydrolysis has been assessed at various levels
of inhibition of CK. Steady state models of CK function
in energy transfer existed but were unable to explain the
dynamic response with CK inhibited.
The aim of this study was to explain the mode of functioning
of the CK system in heart, and in particular the role of different
CK isoenzymes in the dynamic response to workload
steps. For this purpose we used a mathematical model of
cardiac muscle cell energy metabolism containing the kinetics
of the key processes of energy production, consumption
and transfer pathways. The model underscores that CK
plays indeed a dual role in the cardiac cells. The bu ering
role of CK system is due to the activity of myo brillar CK
(MMCK) while the energy transfer role depends on the activity
of mitochondrial CK (MiCK). We propose that this
may lead to the di erences in regulation mechanisms and
energy transfer modes in species with relatively low MiCK
activity such as rabbit in comparison with species with high
MiCK activity such as rat.
The model needed modi cation to explain the new type of
experimental data on the dynamic response of the mitochondria.
We submit that building a Virtual Muscle Cell is not
possible without continuous experimental tests to improve
the model. In close interaction with experiments we are developing
a model for muscle energy metabolism and transport
mediated by the creatine kinase isoforms which now
already can explain many di erent types of experiments.