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Faculty of Biotechnology, Jagiellonian University, Kraków, Poland
Submitted 3 January 2006 ; accepted in final form 20 April 2006
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ABSTRACT |
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 TOP ABSTRACT THEORETICAL PROCEDURESTHEORETICAL RESULTSDISCUSSIONREFERENCES |
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parallel activation; oxidative phosphorylation; transition time; computer model
O2) in the heart rises very quickly during transition from low work to high work: the half-transition time is usually shorter than 10 s and can be as low as 4 s (7, 29). The half-transition time for [PCr] can be even shorter –2.5 s (7, 29). In contrast, the half-transition time for O2 and [PCr] in skeletal muscle at the onset of exercise is much greater: usually between 20 and 65 s (31).
The rate of ATP production by oxidative phosphorylation must be adjusted to the current energy demand to match exactly the rate of ATP consumption. Three main mechanisms of adjusting the rate of ATP supply by oxidative phosphorylation have been proposed in the literature. Because of the first mechanism, which can be called the output-activation mechanism, only the ATP usage block (output of the system) is directly activated by calcium ions (Ca2+) during elevated muscle work, whereas oxidative phosphorylation is activated only indirectly through the negative feedback involving an increase in [ADP] (and [Pi]) (4). The input/output activation mechanism involves the direct activation of substrate dehydrogenation (input of the system), especially the "key" tricarboxylic acid (TCA) cycle dehydrogenases: pyruvate dehydrogenase, isocitrate dehydrogenase, and 2-oxoglutarate dehydrogenase by Ca2+ in parallel with the activation of ATP usage (9, 22). Finally, because of the each-step-activation mechanism or parallel-activation mechanisms, some cytosolic factor (e.g., Ca2+) directly activates all oxidative phosphorylation enzymes, substrate dehydrogenation block, and ATP usage block (13–17). In particular, it has been postulated recently (17) that only the each-step-activation mechanism is able to account for the almost perfect stability of several oxidative phosphorylation metabolites (ADP, PCr, Pi, and NADH) between steady states with very different work intensities and O2 rates in the heart. It was also shown earlier that this mechanism is able to explain many, apparently independent, kinetic properties of oxidative phosphorylation in the skeletal muscle (13–16, 18).
However, in the previous paper (17) concerning the regulation of oxidative phosphorylation in intact mammalian hearts in vivo, only the steady-state properties of the system were analyzed. Therefore, the purpose of the present article is to study in silico the kinetic behavior of oxidative phosphorylation during low-to-high and high-to-low work transitions, assuming different mechanisms of the regulation of oxidative phosphorylation and to confront the theoretical predictions with experimental data obtained in the intact heart and isolated trabeculae under various conditions.
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THEORETICAL PROCEDURES |
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TOPABSTRACTTHEORETICAL PROCEDURESTHEORETICAL RESULTSDISCUSSIONREFERENCES |
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O2 and ATP turnover per unit of heart mass depend on the animal size (both being greater in smaller animals) (see Ref. 17), it is important to stress that this model was developed for middle-size mammals (dogs, pigs, and humans). The discussed model takes into account explicitly the following enzymes/processes/metabolic blocks: substrate dehydrogenation (glycolysis, TCA cycle, fatty acid 
-oxidation, etc.), complex I, complex III, complex IV (cytochrome-c oxidase), proton leak, ATP synthase, ATP/ADP carrier, phosphate carrier, adenylate kinase, creatine kinase, and ATP usage system. The time variations of the metabolite concentrations that constitute independent variables (NADH, ubiquinol, reduced form of cytochrome c, O2, internal protons, internal ATP, internal Pi, external ATP, external ADP, external Pi, external protons, and PCr) are expressed in the form of a set of ordinary differential equations. The set of differential equations is integrated numerically using the Gear procedure. The simulation program is written in FORTRAN. The complete description of the model of oxidative phosphorylation in the intact heart is given in Ref. 17 and is located on the website http://awe.mol.uj.edu.pl/
benio.
Computer simulations.
In the present paper it was assumed that ATP usage at high work is five times greater than at low work (12, 17). The O2 rate equals 2.5 mM/min at low work and 11.2 mM at high work (17). The ratio 11.2/2.5 is slightly lower than 5 because some O2 is due to the proton leak across the inner mitochondrial membrane and not the ATP turnover (within the model the proton leak accounts for 17% and 4% of O2 at low and high work, respectively). The above values of O2 correspond to the minimal and maximal work intensity in the paced intact dog heart in vivo measured in (12), although even higher values of the maximal O2 equal to 12–15 mM/min were found in epinephrine- and phenylephrine-stimulated dog hearts (12). Therefore, it can be estimated that at least a three- to sixfold maximal increase in O2 during low-to-high work transition takes place. However, the present article refers to different experiments performed in different systems (heart in vivo, perfused heart, isolated trabeculae) on hearts of different mammals stimulated in different ways (pacing, isoprenaline administration, adrenaline administration, Ca2+ administration, and increase in sarcomere length). Therefore, the theoretical predictions generated by computer simulations may be in many cases regarded as only semiquantitative ones. Nevertheless, they are useful even when they are able to explain only a given type of behavior of the system.
The fivefold (or, in some cases, twofold) activation/inactivation of ATP usage in computer simulations during low-to-high/high-to-low work transition was equivalent to a fivefold (twofold) increase/decrease in the rate constant of ATP usage. Also in some cases, other components of the system (substrate dehydrogenation and/or particular steps of oxidative phosphorylation) were directly activated/inactivated n times, which corresponded to an n-fold increase/decrease in the appropriate rate constants (or maximal velocities). It was proposed previously that in skeletal muscle the activation/inactivation of the ATP-producing system during rest-to-work/work-to-rest transition is not instant but occurs with some delay (16, 20). An analogous delay, caused by calcium uptake by mitochondria, was proposed for the activation of TCA cycle dehydrogenases in isolated trabeculae (2, 5). Therefore, in some simulations in the present study, the activation/inactivation of substrate dehydrogenation and oxidative phosphorylation during low-to-high/high-to-low work transition was not instant but delayed in time. This delay was expressed by the following equation during low-to-high work transient (16, 20):
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 | (2) |
(ON) and (OFF) are characteristic delay times of activation/inactivation of this step during low-to-high/high-to-low work transition, respectively. Therefore, according to Eqs. 1 and 2, the degree of activation m increases exponentially from 1 to n or decreases exponentially from n to 1 during low-to-high and high-to-low work transition, respectively.
For the purposes of the present in silico studies, the oxidative phosphorylation system was divided into five blocks (subsystems) that are presented in Fig. 1. All components of a given block were always (in)activated to the same extent in computer simulations. These blocks comprise the following: substrate dehydrogenation (DH), oxidation subsystem (OX) (complexes I, III and IV of the respiratory chain), proton leak (LK), phosphorylation subsystem (PH) (ATP synthase, ATP/ADP carrier, Pi carrier), and ATP utilization (UT). DH produces NADH that is oxidized by OX, which is coupled with building up the proton motive force 
p (related to the proton gradient across the inner mitochondrial membrane). Some p is dissipated by LK, but most of it is used for the synthesis (and transport) of ATP, which is in turn used by UT. In different simulations, different blocks were directly activated/inactivated in parallel with the activation/inactivation of ATP usage. The only exception was a proton leak that was never activated during transition to high work, because such an activation would be equivalent to a net energy waste.
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Mode B (input/output activation) represents the input/output activation where ATP usage and substrate dehydrogenation are (instantly) (in)activated to the same extent (5 times), whereas the activity of the remaining blocks remains constant.
Mode C (perfectly balanced each-step activation) represents a perfectly balanced parallel activation of all blocks (each-step activation). This does not mean that all blocks are activated/inactivated to exactly the same extent during low-to-high/high-to-low work transition, but that the concentrations of all metabolites remain constant. Because the pathway is branched at the proton motive force p (some external protons are not used by ATP synthase but by proton leak LK) (compare Fig. 1), PH and UT must be (in)activated slightly more than DH and OX to keep intermediate metabolite concentrations constant. Therefore, a compensation factor (comp) of 0.89 was introduced, and DH and OX were (in)activated in mode C 5·comp (= 4.45) times, whereas PH and UT were (in)activated five times. It must be emphasized that mode C represents an idealized case in which no oxygen diffusion limitations and an instant activation/inactivation of oxidative phosphorylation during on- and off-transient are assumed. This results in an instant increase/decrease in O2 during low-to-high and high-to-low work transition (see below, Fig. 4). This assumption is rather unrealistic, and therefore simulations performed in mode C demonstrate only that the transitions of O2 may be potentially very quick, but not instant, in the real system.
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In mode E (disturbed and delayed each-step activation), the extent of (in)activation of particular blocks is exactly the same as in mode D, but the (in)activation of DH, OX, and PH is delayed in time. For each of these blocks, the characteristic delay times for low-to-high and high-to-low work transition (ON) and (OFF) were equal to 20 and 6 s, respectively. These values were selected to match approximately the experimental data.
In all simulations, the low-work steady-state was maintained for 1 min, energy demand (rate constant of ATP usage) was increased for 2 min to the high-work value, and then energy demand was decreased back to its low-work value.
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THEORETICAL RESULTS |
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TOPABSTRACTTHEORETICAL PROCEDURESTHEORETICAL RESULTSDISCUSSIONREFERENCES |
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O2 and metabolite concentrations are not very quick but occur with some half-transition time t1/2. For instance, this time for both O2 and [PCr] is equal to 14 s during low-to-high work transition. As discussed above, in the simulation presented in Fig. 2, the ATP usage (energy demand) was five times higher at high work than at low work, which is quite a large difference. When a twofold difference in ATP demand was assumed in computer simulations (which resulted in an 1.8-fold difference in O2; compare the above discussion concerning proton leak), the changes in metabolite concentrations were significantly smaller, but still large (for instance [ADP] increased twice), whereas the half-transition times for O2 and [PCr] remained essentially the same (14 s) (computer simulations not shown). Therefore, the transition time for O2 seems to be essentially independent on the work intensity in the stimulated heart.
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O2 and [PCr] are slightly shorter than in mode A and equal 11 s.
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O2 increases or decreases instantly after transition. However, as it is discussed throughout this study, the last property is most probably some idealization of the real system where, e.g., some oxygen diffusion limitations are likely to take place.
When the direct activation of the ATP-producing system was slightly decreased in relation to mode C in the simulation performed in mode D (disturbed parallel activation), some very moderate changes in metabolite concentrations took place, whereas changes in O2 were very quick, although not instant, during low-to-high and high-to-low work transition (Fig. 5). Of course, when the imbalance of parallel activation was increased in mode D (imbalance factor imb was <0.8), the differences between the behavior of the system in mode C and mode D were greater (theoretical results not shown).
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DISCUSSION |
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TOPABSTRACTTHEORETICAL PROCEDURESTHEORETICAL RESULTSDISCUSSIONREFERENCES |
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Computer simulations show that both the output-activation mechanism (mode A, Fig. 2) and input/output activation mechanism (mode B, Fig. 3) generate large changes in metabolite (ADP, PCr, Pi, and NADH) concentrations and half-transition times t1/2 for O2 and [PCr] longer than 10 s. On the other hand, intermediate metabolite concentrations are essentially constant in intact mammalian heart in vivo (1, 10, 12, 26), whereas in perfused hearts and isolated trabeculae relatively moderate changes in metabolite concentrations take place (2, 8, 29, 30). Additionally, the half-transition time for O2 is usually very short in the intact heart. In most cases it equals 4–8 s [and sometimes 11 s (7)] under "normal" physiological conditions (37°C, normoxia, lack of inhibitors) (see Table 2 in Ref. 29), although the transition time may be longer at 20°C or 28°C, in hypoxia or in the presence of inhibitors (7, 29). The last finding is logical because low temperature slows down all biological processes, whereas hypoxia and inhibitors lower the activity of oxidative phosphorylation. Therefore, the computer simulations performed in the present study are relevant to the heart working under "physiological" conditions. In addition, the t1/2 for [PCr] may be even much shorter (about 2.5 s) (29). Therefore, these experimental results cannot be matched by computer simulations performed in modes A and B.
The perfectly balanced parallel-activation (each-step-activation) mechanism (mode C, Fig. 4) predicts no changes in [ADP], [PCr], [Pi], and [NADH]. Therefore, as it was shown previously (17), it is able to explain the perfect stability of these metabolite concentrations at different work intensities encountered in the intact heart in vivo (1, 10, 12, 26). This mechanism also implies that, in the absence of any delay in the activation/inactivation of ATP production, O2 may increase/decrease very quickly (in an idealized case instantly) to its new steady-state value during low-to-high and high-to-low work transition (Fig. 4A), and thus t1/2 for O2 may be very close to zero. However, most probably O2 does not increase/decrease instantly in the real system because of oxygen diffusion limitations. In fact, it was postulated (29) that diffusion limitations are responsible for the significantly shorter t1/2 for [PCr] than for O2. Unfortunately, the time course of O2 has not been measured in the intact heart in vivo. All existing experimental data, especially those discussed in Refs. 7 and 29, concern perfused heart where some changes in metabolite concentrations take place and therefore correspond to mode D. However, the parallel-activation mechanism offers, at least potentially, a possibility of a very quick O2 adjustment during transitions between different steady states with different workloads.
The disturbed parallel-activation mechanism (mode D, Fig. 5) predicts moderate changes in intermediate metabolite concentrations and a short (a few seconds) half-transition time for O2 and [PCr]. Such a kinetic behavior of the system reflects well, at least semiquantitatively, the situation prevailing in many cases in the perfused heart (7, 8, 29, 30). The extent of the changes of metabolite concentrations between low work and high work may depend significantly on the composition of the perfusion medium, for instance, on the respiratory substrates and hormones present in it (8). Therefore, these factors probably determine, at least partly, the size of the imbalance of the parallel activation in the perfused heart.
Finally, computer simulations involving the disturbed parallel-activation mechanism with delayed activation/inactivation of ATP production (mode E, Fig. 6) predict significant overshoots/undershoots in [NADH], [ADP], [PCr], and [Pi]. A very similar [NADH] undershoot during low-to-high work transition and [NADH] overshoot during high-to-low work transition are observed in isolated trabeculae (2) and isolated heart cells (11). Therefore, in this case it seems likely that the activation/inactivation of ATP production is significantly delayed in time. This delay may be due to the transport of calcium through the inner mitochondrial membrane (2, 5) and/or to the kinetics of the activation/inactivation of TCA cycle and oxidative phosphorylation enzymes (16, 20). It is important to emphasize that in isolated trabeculae the steady-state [NADH] differs much more between a steady state with very low, unphysiological stimulation frequency (e.g., 0.25 Hz) and a steady state with a higher, more physiological stimulation frequency (e.g., 1 Hz) than between two steady states with higher stimulation frequencies (e.g., 1 and 3 Hz) (2), as in the simulation presented in Fig. 6. In fact, when the highest stimulation frequencies (4–6 Hz) are applied, NADH level even increases (2). Such a behavior of the system can be reproduced by the model if different degrees of activation of the NADH-producing and NADH-consuming subsystem are assumed (not shown). Unfortunately, changes over time in [ADP], [PCr], and [Pi] during transitions between different stimulation frequencies have not been measured in the discussed experimental system (isolated trabeculae). Significant overshoots/undershoots in these metabolite concentrations, similar to those presented in Fig. 6, were observed in a isoprenaline-stimulated heart (28). However, in this case, they were probably due to a transiently increased work output. The mode E of computer simulations predicts a small overshoot in O2 during low-to-high work transition (see Fig. 6A). However, again, the time course of mitochondrial O2 was not measured in isolated trabeculae, and therefore it is not possible to test this theoretical prediction [it also depends on the characteristic delay time (ON), not shown].
Some experimental results seem to represent intermediate cases between some of the modes defined in the present article. For instance, in electrically paced rat heart cells at 25°C, there is a small [NADH] undershoot during low-to-high work transition and a small overshoot during the opposite transition (Fig. 2 in Ref. 32). Such a behavior is intermediate between modes D and E. In the presence of deoxyglucose there is even some overshoot of [NADH] during low-to-high work transition (Fig. 2 in Ref. 32), whereas steady-state [NADH] remains essentially constant, which suggests a case intermediate between modes B and C (but closer to mode C).
Of course, the five modes of simulations defined in the present study do not exhaust all potential possibilities and combinations of the kinetic properties of the system. For instance, one can imagine mode C (perfectly balanced parallel activation) with some time delay of the activation/inactivation of different steps of ATP production. Additionally, as discussed above, mode C constitutes a certain approximation of the reality and most probably should be supplemented with oxygen diffusion limitations. Maybe the future experimental studies will cause the need of introducing additional modes. However, essentially all experimental data known presently can be reproduced, at least semiquantitatively, within the frame of modes C, D, and E.
Generally, different versions of the parallel-activation mechanism (perfectly balanced, disturbed, disturbed, and delayed) seem to be able to explain the changes in O2 and intermediate metabolite concentrations observed during transitions among different work intensities in the intact heart, perfused hearts, and isolated trabeculae studied in different conditions. Therefore, the idea of parallel activation supplemented with some modifications (some imbalance and/or delay in the activation/inactivation of ATP production) offers a unified theory of the regulation of oxidative phosphorylation during transitions between different work intensities in the heart. In particular, this idea is necessary to explain the short transition times for O2 and [PCr] and very moderate (if any) changes in metabolite concentrations accompanying substantial changes in O2 and work intensity. It seems that, roughly, mode C (supplemented with oxygen diffusion limitations) represents the intact heart in vivo, mode D represents the perfused heart, and mode E represents isolated trabeculae. Therefore, it can be said that the further from the physiological conditions prevailing in vivo, the more disturbed/delayed the parallel activation is.
The half-transition time t1/2 is proportional to the difference in metabolite concentrations between different steady states and inversely proportional to the metabolite flux through the system. Easterby (6) defined the transition time A
B between the initial steady-state A with flux JA and final steady-state B with flux JB in the following way:
 | (3) |
 | (4) |
O2 and [PCr] are generally greater in skeletal muscle [about 20–65 s (31)] than in the heart working under physiological conditions (37°C, normoxia, lack of inhibitors) (2.5–11 s, see Refs. 7 and 29). Namely, changes in intermediate metabolite concentrations during transitions between different work intensities in the heart are smaller than in skeletal muscle, whereas fluxes are higher. Additionally, the computer simulation presented in Fig. 6 (mode E) demonstrates that the transition time depends not only on the changes in metabolite concentrations, but also on the time course of the activation/inactivation of particular components of a considered system. As it was discussed before, the half-transition time t1/2 is not identical with AB. However, AB defined in Eq. 4 is proportional to t1/2.
Cortassa and coworkers (5) developed a computer model of oxidative phosphorylation and TCA cycle involving the calcium-activation of three "key" TCA cycle dehydrogenases (pyruvate dehydrogenase, isocitrate dehydrogenase, and 2-oxoglutarate dehydrogenase). They used their model to study in silico the time course of [NADH] in isolated trabeculae during low-to-high and high-to-low work transition (caused by varying electrical stimulation frequency) (2). They were able to reproduce, at least semiquantitatively, the undershoot in [NADH] during the low-to-high work transition and the overshoot in [NADH] during the opposite transition (5). However, an eightfold increase in stimulation frequency, and thus in ATP usage for contraction and calcium transport, was accompanied in this model by only a very small relative increase in the respiration rate. O2 increased by 20% if it was assumed that the TCA cycle keeps most of the control over the O2 flux. However, it has been demonstrated experimentally that the respiration rate is mostly controlled (under conditions where ATP usage has no control) by oxidative phosphorylation (21), whereas the flux control coefficient for TCA cycle equals about 0.1 (10% of metabolic control). Under this more realistic assumption that the control over O2 is exerted predominantly by oxidative phosphorylation, the respiration rate in the model developed by Cortassa and coworkers increases by only 10% (5). This example shows very clearly that, first, many different models can be adjusted by manipulating with assumptions and free parameter values to some simple set of experimental data, and therefore, second, any model should be thoroughly validated by comparison of its predictions with possibly a great number of different parameter values and system properties. The computer simulation shown in Fig. 6 demonstrates that both the undershoot/overshoot in [NADH] and a substantial increase/decrease in O2 during low-to-high/high-to-low work transition can be predicted by a computer model when the delayed-and-disturbed parallel-activation mechanism (mode E) and not the delayed input/output-activation mechanism used by Cortassa and coworkers is applied (in fact, in the model by Cortassa and coworkers there is no ATP usage but only a pulse of ADP introduced ad hoc to force the expected behavior of the system).
The parallel activation of different steps of the ATP-producing system seems to develop gradually as an animal matures, because in young sheep, changes in metabolite concentrations between different work intensities are significantly greater than in adult sheep (24). It was shown earlier that the each-step-activation mechanism is able to explain many, apparently unrelated to each other, kinetic properties of oxidative phosphorylation in the skeletal muscle (13–16, 18). These properties comprise 1) the relative stability of [ADP], [Pi], PCr/Cr, NADH/NAD+, and p during rest-to-work transition (13, 16); 2) the much steeper phenomenological O2/[ADP] relationship in the intact skeletal muscle than in isolated muscle mitochondria (13, 16); 3) the two to four (to six) times greater maximum oxygen consumption in intact skeletal muscle than in isolated mitochondria, skinned fibers, or muscle homogenate when scaled for the amount of mitochondrial proteins (18, 25, 27); 4) the increase in the relative slope of the phenomenological O2/[ADP] relationship as a result of muscle training (19); 5) the greater O2 at a given [ADP] and amount of mitochondrial protein in trained muscle than in untrained muscle and in untrained muscle than in hypothyroid muscle (16); 6) the asymmetry of the half-transition time t1/2 for [PCr] between the on-transient (rest-to-work transition) and off-transient (work-to-rest transition) (16); and 7) the PCr recovery overshoot (16) and the variability of the kinetic properties of oxidative phosphorylation in different muscles and various experimental conditions (16). Therefore, the idea of the each-step activation in both heart and skeletal muscle seems to be well founded. The differences in the regulation of oxidative phosphorylation between these tissues are discussed in Ref. 17.
The parallel-activation mechanism implies that the potential capacity of oxidative phosphorylation for ATP synthesis in the intact heart is significantly higher than the maximal ATP synthesis rate by isolated mitochondria (when scaled for the amount of mitochondrial proteins). In intact skeletal muscle the maximal O2 is two to six times greater than in isolated mitochondria (18, 25, 27). On the other hand, Mootha and coworkers (23) reported that the hearts of the exercising dog and pig use only up to 80–90% of the maximal oxidative phosphorylation capacity in isolated heart mitochondria. However, the maximal O2 in mitochondria was measured at saturating concentrations of ADP, Pi, oxygen, and respiratory substrates. On the other hand, [ADP] in intact heart in vivo is around the Km value of oxidative phosphorylation for ADP and is essentially constant even during transition to very high work intensities (12). Also [Pi] is constant and not saturating (12). Furthermore, it is very likely that at high work intensities in the intact heart, oxygen and respiratory substrate supply by blood becomes limiting for O2 and ATP synthesis by oxidative phosphorylation. Taken together, the above properties of the system in vivo suggest that the "true" (potential) capacity of oxidative phosphorylation in the intact heart is at least twice (and perhaps much more) greater than in isolated mitochondria, in accordance with the idea of parallel activation.
The physical nature of the factor(s)/mechanism(s) X responsible for the direct parallel activation of (particular components of) the oxidative phosphorylation system during low-to-high work transition remains unclear. Several evidences suggest some involvement of Ca2+. However, it is not certain whether a high calcium concentration is the (only) factor looked for. It has been proposed (14) that the relevant factor may be the frequency of calcium oscillations. This frequency could be integrated over time by some protein, analogous to calmodulin, that is lost or inactivated during isolation of mitochondria. On the other hand, the fact that ruthenium red, an inhibitor of Ca2+ uptake by mitochondria, only slightly lengthens the low-to-high work transition but does not affect much the steady-state metabolite concentrations (28) suggests that either this inhibitor only delays but does not block calcium entry into mitochondria, or there exists another factor/mechanism that acts in parallel with Ca2+. There is also a possibility that, whereas TCA cycle dehydrogenases are activated by matrix calcium, the oxidative phosphorylation complexes, being transmembrane proteins located in the inner mitochondrial membrane, are activated by cytosolic calcium and therefore do not need the Ca2+ transport to the matrix for their activation.
Of course, the computer model used in the present study contains several simplifications. For instance, as discussed above, it does not take into account the possible oxygen diffusion limitations that can delay O2 transitions in the real system. Additionally, the NADH-producing system is described by a simple phenomenological equation. Theoretical studies using a model containing a more sophisticated description of this system demonstrated that rapid activation of glycolysis and cytosolic NADH formation may be important in the transition to high work states in the heart (33, 34).
In summary, the present theoretical study demonstrates that the parallel-activation mechanism of the adjustment of ATP production to the present energy demand is able to explain, at least in principle, different kinds of the dynamic behavior of the oxidative phosphorylation system (changes over time of O2 and intermediate metabolite concentrations) encountered in different experimental conditions during low-to-high and high-to-low work transitions. Generally, under physiological conditions (intact heart in vivo) the direct activation of particular elements of the ATP-producing system (substrate dehydrogenation and oxidative phosphorylation) in parallel with the activation of ATP usage during transition from low work to high work seems to be perfectly balanced and not significantly delayed in time. In less physiological conditions (perfused heart, isolated trabeculae), this parallel activation is likely to be disturbed (ATP production is activated slightly less than ATP consumption) and/or delayed (it takes some time to activate/inactivate TCA cycle and oxidative phosphorylation). However, in all the analyzed cases a direct activation/inactivation of particular oxidative phosphorylation complexes during low-to-high/high-to-low work transition is needed to reproduce the experimental data.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTTHEORETICAL PROCEDURESTHEORETICAL RESULTSDISCUSSIONREFERENCES |
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  Y. Li, R. K. Dash, J. Kim, G. M. Saidel, and M. E. Cabrera Role of NADH/NAD+ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies Am J Physiol Cell Physiol, January 1, 2009; 296(1): C25 - C46. [Abstract] [Full Text] [PDF]
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 L. Zhou, M. E. Cabrera, H. Huang, C. L. Yuan, D. K. Monika, N. Sharma, F. Bian, and W. C. Stanley Parallel activation of mitochondrial oxidative metabolism with increased cardiac energy expenditure is not dependent on fatty acid oxidation in pigs J. Physiol., March 15, 2007; 579(3): 811 - 821. [Abstract] [Full Text] [PDF]
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