Аннотация
An intricate network of reactions is involved in matching energy supply
with demand in the heart. This complexity arises because energy production
both modulates and is modulated by the electrophysiological and contractile
activity of the cardiac myocyte. Here, we present an integrated mathematical
model of the cardiac cell that links excitation-contraction coupling
with mitochondrial energy generation. The dynamics of the model are
described by a system of 50 ordinary differential equations. The
formulation explicitly incorporates cytoplasmic ATP-consuming processes
associated with force generation and ion transport, as well as the
creatine kinase reaction. Changes in the electrical and contractile
activity of the myocyte are coupled to mitochondrial energetics through
the ATP, Ca$^2+$, and Na$^+$ concentrations in the myoplasmic
and mitochondrial matrix compartments. The pseudo steady-state relationship
between force and oxygen consumption at various stimulus frequencies
and external Ca$^2+$ concentrations is reproduced in both model
simulations and direct experiments in cardiac trabeculae under normoxic
conditions, recapitulating the linearity between cardiac work and
respiration in the heart. Importantly, the model can also reproduce
the rapid time-dependent changes in mitochondrial NADH and Ca$^2+$
in response to abrupt changes in workload. The steady-state and dynamic
responses of the model were conferred by ADP-dependent stimulation
of mitochondrial oxidative phosphorylation and Ca$^2+$ -dependent
regulation of Krebs cycle dehydrogenases, illustrating how the model
can be used as a tool for investigating mechanisms underlying metabolic
control in the heart.
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