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Roles of the creatine kinase system and myoglobin in maintaining energetic state in the working heart.

Wu F, Beard DA - BMC Syst Biol (2009)

Bottom Line: The heart is capable of maintaining contractile function despite a transient decrease in blood flow and increase in cardiac ATP demand during systole.In contrast, disabling the creatine kinase system results in considerable oscillations of cytoplasmic ADP and ATP levels and seriously deteriorates the stability of DeltaGATPase in the beating heart.The CK system stabilizes DeltaGATPase by both buffering ATP and ADP concentrations and enhancing the feedback signal of inorganic phosphate in regulating mitochondrial oxidative phosphorylation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. fwu@mcw.edu

ABSTRACT

Background: The heart is capable of maintaining contractile function despite a transient decrease in blood flow and increase in cardiac ATP demand during systole. This study analyzes a previously developed model of cardiac energetics and oxygen transport to understand the roles of the creatine kinase system and myoglobin in maintaining the ATP hydrolysis potential during beat-to-beat transient changes in blood flow and ATP hydrolysis rate.

Results: The theoretical investigation demonstrates that elimination of myoglobin only slightly increases the predicted range of oscillation of cardiac oxygenation level during beat-to-beat transients in blood flow and ATP utilization. In silico elimination of myoglobin has almost no impact on the cytoplasmic ATP hydrolysis potential (DeltaGATPase). In contrast, disabling the creatine kinase system results in considerable oscillations of cytoplasmic ADP and ATP levels and seriously deteriorates the stability of DeltaGATPase in the beating heart.

Conclusion: The CK system stabilizes DeltaGATPase by both buffering ATP and ADP concentrations and enhancing the feedback signal of inorganic phosphate in regulating mitochondrial oxidative phosphorylation.

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Transient changes of myoglobin saturation, phosphate levels, cytoplasmic ATP hydrolysis potential, mitochondrial inner membrane potential, and mitochondrial ATP production rate in the control system. (A.) Myoglobin saturation (SMb). (B.) Cytoplasmic ATP concentration ([ATP]c). (C.) Cytoplasmic creatine phosphate concentration ([CrP]c). (D.) Cytoplasmic inorganic phosphate concentration ([Pi]c). (E.) Cytoplasmic ADP concentration ([ADP]c). (F.) Cytoplasmic ATP hydrolysis potential (-ΔGATPase). (G.) Mitochondrial inner membrane potential (ΔΨ). (H.) Mitochondrial ATP production rate, equal to mitochondrial adenosine nucleotide translocator flux (JANT). All variables are simulated for the time courses of the flow and ATP consumption rate in Figure 3.
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Figure 4: Transient changes of myoglobin saturation, phosphate levels, cytoplasmic ATP hydrolysis potential, mitochondrial inner membrane potential, and mitochondrial ATP production rate in the control system. (A.) Myoglobin saturation (SMb). (B.) Cytoplasmic ATP concentration ([ATP]c). (C.) Cytoplasmic creatine phosphate concentration ([CrP]c). (D.) Cytoplasmic inorganic phosphate concentration ([Pi]c). (E.) Cytoplasmic ADP concentration ([ADP]c). (F.) Cytoplasmic ATP hydrolysis potential (-ΔGATPase). (G.) Mitochondrial inner membrane potential (ΔΨ). (H.) Mitochondrial ATP production rate, equal to mitochondrial adenosine nucleotide translocator flux (JANT). All variables are simulated for the time courses of the flow and ATP consumption rate in Figure 3.

Mentions: Figure 4 illustrates transient changes of myoglobin saturation level (SMb), phosphate metabolite levels, cytoplasmic ATP hydrolysis potential (ΔGATPase), mitochondrial inner membrane potential (ΔΨ), and mitochondrial ANT transport flux (JANT), following a step change of cardiac workload and coronary blood flow (shown in Figure 3) in the normal system. The ANT transport flux is the rate at which ATP is transported from the mitochondrial matrix to the cytoplasm in exchange for ADP. When the step change in work rate occurs at time t = 6 seconds, these variables move from their baseline steady state values to approach new steady-state values at the maximal workload after about 20 seconds. Average SMb decreases from 0.94 to 0.91, average [ATP]c remains almost constant (slightly decreasing from ~9.66 to ~9.64 mM), average [CrP]c decreases from ~23.4 to ~19.5 mM, average [Pi]c increases from ~0.28 to ~2.1 mM, average [ADP]c increases from ~42 to ~62 μm, average -ΔGATPase decreases from ~70.2 to ~63.5 kJ mol-1, average ΔΨ decreases from ~180 to ~174 mV, and average JANT increases from 0.36 to 1.2 mmol s-1 (l cell)-1. The range of oscillation of the variables in SMb, [ATP]c, [CrP]c, [Pi]c, [ADP]c, and JANT increases slightly, but interestingly, the oscillations of -ΔGATPase and ΔΨ slightly decrease, implying that despite elevated instability of oxygenation and phosphate metabolite levels, energetic stability is slightly increased with increasing work rate.


Roles of the creatine kinase system and myoglobin in maintaining energetic state in the working heart.

Wu F, Beard DA - BMC Syst Biol (2009)

Transient changes of myoglobin saturation, phosphate levels, cytoplasmic ATP hydrolysis potential, mitochondrial inner membrane potential, and mitochondrial ATP production rate in the control system. (A.) Myoglobin saturation (SMb). (B.) Cytoplasmic ATP concentration ([ATP]c). (C.) Cytoplasmic creatine phosphate concentration ([CrP]c). (D.) Cytoplasmic inorganic phosphate concentration ([Pi]c). (E.) Cytoplasmic ADP concentration ([ADP]c). (F.) Cytoplasmic ATP hydrolysis potential (-ΔGATPase). (G.) Mitochondrial inner membrane potential (ΔΨ). (H.) Mitochondrial ATP production rate, equal to mitochondrial adenosine nucleotide translocator flux (JANT). All variables are simulated for the time courses of the flow and ATP consumption rate in Figure 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667476&req=5

Figure 4: Transient changes of myoglobin saturation, phosphate levels, cytoplasmic ATP hydrolysis potential, mitochondrial inner membrane potential, and mitochondrial ATP production rate in the control system. (A.) Myoglobin saturation (SMb). (B.) Cytoplasmic ATP concentration ([ATP]c). (C.) Cytoplasmic creatine phosphate concentration ([CrP]c). (D.) Cytoplasmic inorganic phosphate concentration ([Pi]c). (E.) Cytoplasmic ADP concentration ([ADP]c). (F.) Cytoplasmic ATP hydrolysis potential (-ΔGATPase). (G.) Mitochondrial inner membrane potential (ΔΨ). (H.) Mitochondrial ATP production rate, equal to mitochondrial adenosine nucleotide translocator flux (JANT). All variables are simulated for the time courses of the flow and ATP consumption rate in Figure 3.
Mentions: Figure 4 illustrates transient changes of myoglobin saturation level (SMb), phosphate metabolite levels, cytoplasmic ATP hydrolysis potential (ΔGATPase), mitochondrial inner membrane potential (ΔΨ), and mitochondrial ANT transport flux (JANT), following a step change of cardiac workload and coronary blood flow (shown in Figure 3) in the normal system. The ANT transport flux is the rate at which ATP is transported from the mitochondrial matrix to the cytoplasm in exchange for ADP. When the step change in work rate occurs at time t = 6 seconds, these variables move from their baseline steady state values to approach new steady-state values at the maximal workload after about 20 seconds. Average SMb decreases from 0.94 to 0.91, average [ATP]c remains almost constant (slightly decreasing from ~9.66 to ~9.64 mM), average [CrP]c decreases from ~23.4 to ~19.5 mM, average [Pi]c increases from ~0.28 to ~2.1 mM, average [ADP]c increases from ~42 to ~62 μm, average -ΔGATPase decreases from ~70.2 to ~63.5 kJ mol-1, average ΔΨ decreases from ~180 to ~174 mV, and average JANT increases from 0.36 to 1.2 mmol s-1 (l cell)-1. The range of oscillation of the variables in SMb, [ATP]c, [CrP]c, [Pi]c, [ADP]c, and JANT increases slightly, but interestingly, the oscillations of -ΔGATPase and ΔΨ slightly decrease, implying that despite elevated instability of oxygenation and phosphate metabolite levels, energetic stability is slightly increased with increasing work rate.

Bottom Line: The heart is capable of maintaining contractile function despite a transient decrease in blood flow and increase in cardiac ATP demand during systole.In contrast, disabling the creatine kinase system results in considerable oscillations of cytoplasmic ADP and ATP levels and seriously deteriorates the stability of DeltaGATPase in the beating heart.The CK system stabilizes DeltaGATPase by both buffering ATP and ADP concentrations and enhancing the feedback signal of inorganic phosphate in regulating mitochondrial oxidative phosphorylation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. fwu@mcw.edu

ABSTRACT

Background: The heart is capable of maintaining contractile function despite a transient decrease in blood flow and increase in cardiac ATP demand during systole. This study analyzes a previously developed model of cardiac energetics and oxygen transport to understand the roles of the creatine kinase system and myoglobin in maintaining the ATP hydrolysis potential during beat-to-beat transient changes in blood flow and ATP hydrolysis rate.

Results: The theoretical investigation demonstrates that elimination of myoglobin only slightly increases the predicted range of oscillation of cardiac oxygenation level during beat-to-beat transients in blood flow and ATP utilization. In silico elimination of myoglobin has almost no impact on the cytoplasmic ATP hydrolysis potential (DeltaGATPase). In contrast, disabling the creatine kinase system results in considerable oscillations of cytoplasmic ADP and ATP levels and seriously deteriorates the stability of DeltaGATPase in the beating heart.

Conclusion: The CK system stabilizes DeltaGATPase by both buffering ATP and ADP concentrations and enhancing the feedback signal of inorganic phosphate in regulating mitochondrial oxidative phosphorylation.

Show MeSH