The Role of Ca~(2+)in Coupling Cardiac Metabolism with Regulation of Contraction In Silico Modeling

摘要

The heart adapts the rate of mitochondrial ATP production to energy demand without noticeablechanges in the concentration of ATP, ADP and Pi, even for large transitions between differentworkloads. We suggest that the changes in demand modulate the cytosolic Ca~(2+)concentration thatchanges mitochondrial Ca~(2+) to regulate ATP production. Thus, the rate of ATP production by themitochondria is coupled to the rate of ATP consumption by the sarcomere cross-bridges (XBs).An integrated model was developed to couple cardiac metabolism and mitochondrial ATP pro-duction with the regulation of Ca~(2+)transient and ATP consumption by the sarcomere. The modelincludes two interrelated systems that run simultaneously utilizing two different integration steps:(1) The faster system describes the control of excitation contraction coupling with fast cytosolicCa~(2+) transients, twitch mechanical contractions, and associated fluctuations in the mitochondrialCa~(2+).(2) A slower system simulates the metabolic system, which consists of three different com-partments: blood, cytosol, and mitochondria. The basic elements of the model are dynamic massbalances in the different compartments. Cytosolic Ca~(2+) handling is determined by four organelles:sarcolemmal Ca~(2+)influx and efflux;sarcoplasmic reticulum(SR) Ca~(release sequestration(SR); binding and dissociation from sarcomeric regulatory troponin complexes; and mitochondrialCa~(2+)flows. Mitochondrial Ca~(flows are determined by the uniporter and mitochondrialNa~+Ca~(2+) exchanger. The cytosolic Ca~(2+)determines the rate of ATP consumption by the sarcom-ere. Ca~(2+)binding to troponin regulates the rate of XBs recruitment and force development. Themitochondrial Ca~(2+)concentration determines the pyruvate dehydrogenase activity and the rate ofATP production by the F_1-F_0 ATPase. The workload modulates the cytosolic Ca~(2+)concentrationthrough feedback loops. The preload and afterload affect the number of strong XBs. The number ofstrong XBs determines the affinity of troponin for Ca~(2+), which alters the cytosolic Ca~(2+) transient.Model simulations quantify the role of Ca~(2+)in simultaneously controlling the power of contractionand the rate of ATP production. It explains the established empirical observation that significantchanges in the metabolic fluxes can occur without significant changes in the key nucleotide (ATPand ADP) concentrations. Quantitative investigations of the mechanisms underlying the cardiaccontrol of biochemical to mechanical energy conversion may lead to novel therapeutic modalitiesfor the ischemic and failing myocardium.