Biomedical subjects

Bernard Korzeniewski

Publications and source records attributed to Bernard Korzeniewski.

At least 19 recordsLinked to original sources

PubMed2006

Metabolic control over the oxygen consumption flux in intact skeletal muscle: in silico studies.

It has been postulated previously that a direct activation of all oxidative phosphorylation complexes in parallel with the activation of ATP usage and substrate dehydrogenation (the so-called each-step activation) is the main mechanism responsible for adjusting the rate of ATP production by mitochondria to the current energy demand during rest-to-work transition in intact skeletal muscle in vivo. The present in silico study, using a computer model of oxidative phosphorylation developed previously, analyzes the impact of the each-step-activation mechanism on the distribution of control (defined within Metabolic Control Analysis) over the oxygen consumption flux among the components of the bioenergetic system in intact oxidative skeletal muscle at different energy demands. It is demonstrated that in the absence of each-step activation, the oxidative phosphorylation complexes take over from ATP usage most of the control over the respiration rate and oxidative ATP production at higher (but still physiological) energy demands. This leads to a saturation of oxidative phosphorylation, impossibility of a further acceleration of oxidative ATP synthesis, and dramatic drop in the phosphorylation potential. On the other hand, the each-step-activation mechanism allows maintenance of a high degree of the control exerted by ATP usage over the ATP turnover and oxygen consumption flux even at high energy demands and thus enables a potentially very large increase in ATP turnover. It is also shown that low oxygen concentration shifts the metabolic control from ATP usage to cytochrome oxidase and thus limits the oxidative ATP production.

Adenosine Triphosphate↗

PubMed2006

Oxygen consumption and metabolite concentrations during transitions between different work intensities in heart.

Steady-state metabolite (ADP, ATP, P(i), PCr, and NADH) concentrations usually differ little between different workloads with significantly different oxygen consumption rates in the heart. However, during transitions between steady states, metabolite concentrations may in some cases change transiently, exhibiting a significant overshoot or undershoot, whereas in other cases they approach near-exponentially new steady-state values. Oxygen consumption rate usually reaches the new steady-state value very quickly (within a few seconds). The present in silico studies, performed using a previously developed computer model of oxidative phosphorylation in the heart, demonstrate that such a behavior of the oxidative phosphorylation system can be reproduced only under the assumption that ATP usage, substrate dehydrogenation, and (particular steps of) oxidative phosphorylation are directly activated to a similar extend by some cytosolic factor/mechanism during transition from low work to high work (the so-called parallel-activation mechanism). Computer simulations show that some differences observed between different experimental systems can be explained by a slightly different balance of the activation of particular components of the system and/or by a delay in time of the activation/inactivation of substrate dehydrogenation and oxidative phosphorylation during low-to-high and high-to-low work transitions. Thus the presented theoretical approach offers a general idea that is able to unify, at least semiquantitatively, different experimental data available in the literature.

Adenosine Triphosphate↗

PubMed2006

Biochemical background of the VO2 on-kinetics in skeletal muscles.

This review discusses the present knowledge on the oxygen uptake kinetics at the onset of exercise in skeletal muscle and the contribution of a previously developed computer model of oxidative phosphorylation in intact skeletal muscle to the understanding of the factors determining this kinetics on the biochemical level. It has been demonstrated recently that an increase in the total creatine pool [PCr + Cr] and in glycolytic ATP supply lengthen the half-transition time of the VO2 on-kinetics, while an increase in mitochondria content, in parallel activation of ATP supply and ATP usage, in muscle oxygen concentration, in proton leak, in resting energy demand, in resting cytosolic pH, and in initial alkalization diminish this parameter. It has also been shown that the half-transition time is near-linearly proportional to the absolute difference between the phosphocreatine concentration during work and at rest (deltaPCr). The present review discusses whether the V/O2 on-kinetics on the muscle level is strictly or only approximately exponential. Finally, it is postulated that a short transition time of the VO2 on-kinetics in itself does not need be profitable for the skeletal muscle functioning during exercise, but usually a short transition time is correlated with factors that improve exercise capacity. The transition time is a phenomenological parameter resulting from the biochemical properties of the system and not a physical factor that can cause anything in the system.

Adenosine Triphosphate↗

PubMed2005

AMP deamination delays muscle acidification during heavy exercise and hypoxia.

In silico studies carried out by using a computer model of oxidative phosphorylation and anaerobic glycolysis in skeletal muscle demonstrated that deamination of AMP to IMP during heavy short term exercise and/or hypoxia lessens the acidification of myocytes. The concerted action of adenylate kinase and AMP deaminase, leading to a decrease in the total adenine nucleotide pool, constitutes an additional process consuming ADP and producing ATP. It diminishes the amount of ADP that must be converted to ATP by other processes in order to meet the rate of ADP production by ATPases (because the adenylate kinase + AMP deaminase system produces only 1 ATP per 2 ADPs used, ATP consumption is not matched by ATP production, and the reduction of the total adenine nucleotide pool occurs mostly at the cost of [ATP]). As a result, the rate of ADP consumption by other processes may be lowered. This effect concerns mostly ADP consumption by anaerobic glycolysis that is inhibited by AMP deamination-induced decrease in [ADP] and [AMP], and not oxidative phosphorylation, because during heavy exercise and/or hypoxia [ADP] is significantly greater than the Km value of this process for ADP. The resultant reduction of proton production by anaerobic glycolysis enables us to delay the termination of exercise because of fatigue and/or to diminish cell damage.

AMP Deaminase↗

PubMed2005

Regulation of oxidative phosphorylation in intact mammalian heart in vivo.

A dynamic computer model of oxidative phosphorylation in intact heart was developed by modifying the model of oxidative phosphorylation in intact skeletal muscle published previously. Next, this model was used for theoretical studies on the regulation of oxidative phosphorylation in intact heart in vivo during transition between different work intensities. It is shown that neither a direct activation of ATP usage alone nor a direct activation of both ATP usage and substrate dehydrogenation, including the calcium-activated tricarboxylate acid cycle dehydrogenases, can account for the constancy of [ADP], [PCr], [P(i)] and [NADH] during a significant increase in oxygen consumption and ATP turnover encountered in intact heart in vivo. Only a direct activation of all oxidative phosphorylation complexes in parallel with a stimulation of ATP usage and substrate dehydrogenation enabled to reproduce the experimental data concerning the constancy of metabolite concentrations. The molecular background of the differences between heart and skeletal muscle in the kinetic behaviour of the oxidative phosphorylation system is also discussed.

Adenosine Triphosphate↗

PubMed2005

Some factors determining the PCr recovery overshoot in skeletal muscle.

It has been proposed recently that the phosphocreatine (PCr) overshoot (increase above the resting level) during muscle recovery after exercise is caused by a slow decay during this recovery of the direct activation of oxidative phosphorylation taking place during muscle work. In the present article the factors determining the appearance and size of the PCr overshoot are studied using the computer model of oxidative phosphorylation in intact skeletal muscle developed previously. It is demonstrated that the appearance and duration of this overshoot is positively correlated with the value of the characteristic decay time of the direct activation of oxidative phosphorylation. It is also shown that the size of PCr overshoot is increased by low resting PCr/Cr ratio (what is confirmed by our unpublished experimental data), by high intensity of the direct activation of oxidative phosphorylation, by high muscle work intensity and by low rate of the return of cytosolic pH to the resting value during muscle recovery.

Adenosine Diphosphate↗

PubMed2005

Confrontation of the cybernetic definition of a living individual with the real world.

The cybernetic definition of a living individual proposed previously (Korzeniewski, 2001) is very abstract and therefore describes the essence of life in a very formal and general way. In the present article this definition is reformulated in order to determine clearly the relation between life in general and a living individual in particular, and it is further explained and defended. Next, the cybernetic definition of a living individual is confronted with the real world. It is demonstrated that numerous restrictions imposed on the cybernetic definition of life by physical reality imply a number of particular properties of life that characterize present life on Earth, namely: (1) a living individual must be a dissipative structure (and therefore a low-entropy thermodynamic system out of the state of equilibrium); (2) spontaneously-originated life must be based on organic compounds; (3) evolutionarily stable self-dependent, free-living individuals must have some minimal level of complexity of structure and function; (4) a living individual must have a record of identity separated from an executive machinery; (5) the identity of living individuals must mutate and may evolve; (6) living individuals may collect and accumulate information in subsequent generations over very long periods of time; (7) the degree of complexity of a living individual reflects the degree of complexity of its environment (ecological niche) and (8) living individuals are capable of supple adaptation to varying environmental conditions. Thus, the cybernetic definition of a living individual, when confronted with the real physical world, generates most of the general properties of the present life on Earth.

Biological Evolution↗

PubMed2004

Preexercise metabolic alkalosis induced via bicarbonate ingestion accelerates Vo2 kinetics at the onset of a high-power-output exercise in humans.

The present study investigated the effect of preexercise metabolic alkalosis on the primary component of oxygen uptake (Vo(2)) kinetics, characterized by tau(1). Seven healthy physically active nonsmoking men, aged 22.4 +/- 1.8 (mean +/- SD) yr, maximum Vo(2) (Vo(2 max)) 50.4 +/- 4 ml.min(-1).kg(-1), performed two bouts of cycling, corresponding to 40 and 87% of Vo(2 max), lasting 6 min each, separated by a 20-min pause, once as a control study and a few days later at approximately 90 min after ingestion of 3 mmol/kg body wt of NaHCO(3). Blood samples for measurements of bicarbonate concentration and hydrogen ion concentration were taken from antecubital vein via catheter. Pulmonary Vo(2) was measured continuously breath by breath. The values of tau(1) were calculated by using six various approaches published in the literature. Preexercise level of bicarbonate concentration after ingestion of NaHCO(3) was significantly elevated (P < 0.01) compared with the control study (28.96 +/- 2.11 vs. 24.84 +/- 1.18 mmol/l; P < 0.01), and [H(+)] was significantly (P < 0.01) reduced (42.79 +/- 3.38 nmol/l vs. 46.44 +/- 3.51 nmol/l). This shift (P < 0.01) was also present during both bouts of exercise. During cycling at 40% of Vo(2 max), no significant effect of the preexercise alkalosis on the magnitude of tau(1) was found. However, during cycling at 87% of Vo(2 max), the tau(1) calculated by all six approaches was significantly (P < 0.05) reduced, compared with the control study. The tau(1) calculated as in Borrani et al. (Borrani F, Candau R, Millet GY, Perrey S, Fuchsloscher J, and Rouillon JD. J Appl Physiol 90: 2212-2220, 2001) was reduced on average by 7.9 +/- 2.6 s, which was significantly different from zero with both the Student's t-test (P = 0.011) and the Wilcoxon's signed-ranks test (P = 0.014).

Administration, Oral↗

PubMed2004

Theoretical studies on the regulation of anaerobic glycolysis and its influence on oxidative phosphorylation in skeletal muscle.

It is shown, using the computer model of glycolysis in skeletal muscle developed recently by Lambeth and Kushmerick (Ann. Biomed. Bioenerg, 30 (2001) 19-34) incorporated into the computer model of oxidative phosphorylation developed by Korzeniewski et al. (Biophys. Chem. 83 (2001) 19-34) that the regulation of glycolysis by ADP, AMP and P(i) is decidedly insufficient to explain the large increase in the glycolytic flux during transition from rest to intensive exercise in intact skeletal muscle. Computer simulations based on a simple kinetic description of the glycolytic ATP and H(+) production strongly suggests that glycolysis must be directly activated during muscle contraction. They also demonstrate that the inhibition of glycolysis by H(+) is needed to explain the transient activation of this pathway at the onset of exercise as well as the duration time and extent of the initial alkalization after the onset of exercise. Finally, it is shown that ATP supply from anaerobic glycolysis slows down the VO(2) kinetics during rest-to-work transition.

Adenosine Diphosphate↗

PubMed2004

Factors determining the oxygen consumption rate (VO2) on-kinetics in skeletal muscles.

Using a computer model of oxidative phosphorylation developed previously [Korzeniewski and Mazat (1996) Biochem. J. 319, 143-148; Korzeniewski and Zoladz (2001) Biophys. Chem. 92, 17-34], we analyse the effect of several factors on the oxygen-uptake kinetics, especially on the oxygen consumption rate (VO2) and half-transition time t(1/2), at the onset of exercise in skeletal muscles. Computer simulations demonstrate that an increase in the total creatine pool [PCr+/-Cr] (where Cr stands for creatine and PCr for phosphocreatine) and in glycolytic ATP supply lengthen the half-transition time, whereas increase in mitochondrial content, in parallel activation of ATP supply and ATP usage, in oxygen concentration, in proton leak, in resting energy demand, in resting cytosolic pH and in initial alkalization decrease this parameter. Theoretical studies show that a decrease in the activity of creatine kinase (CK) [displacement of this enzyme from equilibrium during on-transient (rest-to-work transition)] accelerates the first stage of the VO2 on-transient, but slows down the second stage of this transient. It is also demonstrated that a prior exercise terminated a few minutes before the principal exercise shortens the transition time. Finally, it is shown that at a given ATP demand, and under conditions where CK works near the thermodynamic equilibrium, the half-transition time of VO2 kinetics is determined by the amount of PCr that has to be transformed into Cr during rest-to-work transition; therefore any factor that diminishes the difference in [PCr] between rest and work at a given energy demand will accelerate the VO2 on-kinetics. Our conclusions agree with the general idea formulated originally by Easterby [(1981) Biochem. J. 199, 155-161] that changes in metabolite concentrations determine the transition times between different steady states in metabolic systems.

Adenosine Triphosphate↗

PubMed2004

The modeling of oxidative phosphorylation in skeletal muscle.

A computer model of oxidative phosphorylation was developed in isolated muscle mitochondria [Korzeniewski and Mazat: Biochem J 319: 143-148, 1996] and in intact skeletal muscle [Korzeniewski and Zoladz: Biophys Chem 92: 17-34, 2001]. Within this model the dependence on different metabolite concentrations of the rate of each enzymatic reaction, process and flux is described by an appropriate kinetic equation. The changes of metabolite concentrations over time are described by a set of ordinary differential equations. The model has been very extensively tested by a comparison of computer simulations with a broad set of experimental results concerning various kinetic properties of the oxidative phosphorylation system. Next the model was used for theoretical studies on the regulation of oxidative phosphorylation in intact muscle cells. The model decidedly supports the so-called parallel-activation mechanism or each-step-activation mechanism of adjusting the rate of ATP supply to the current energy demand [Korzeniewski: Biochem J 330: 1189-1195, 1998; Korzeniewski: Biochem J 375: 799-804, 2003]. Because of this mechanism, not only ATP usage, but also the substrate dehydrogenation system and all oxidative phosphorylation complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, phosphate carrier) are directly (and not by changes in metabolite concentrations) activated by some intracellular factor(s) related to muscle contraction, probably by calcium ions, during the transition from rest to work. This mechanism is able to account for several kinetic properties of oxidative phosphorylation that cannot be explained by other mechanisms postulated in the literature. Thus the discussed kinetic model of oxidative phosphorylation has appeared to be a very useful research tool.

Animals↗

PubMed2003

Regulation of oxidative phosphorylation in different muscles and various experimental conditions.

It has been shown previously that direct stimulation of oxidative-phosphorylation complexes in parallel with the stimulation of ATP usage is able to explain the stability of intermediate metabolite (ATP/ADP, phosphocreatine/creatine, NADH/NAD+, protonmotive force) concentrations accompanied by a large increase in oxygen consumption and ATP turnover during transition from rest to intensive exercise in skeletal muscle. It has been also postulated that intensification of parallel activation in the ATP supply-demand system is one of the mechanisms of training-induced adaptation of oxidative phosphorylation in skeletal muscle. In the present paper, it is demonstrated, using the computer model of oxidative phosphorylation in intact skeletal muscle developed previously, that the direct activation of oxidative phosphorylation during muscle contraction can account for the following kinetic properties of oxidative phosphorylation in skeletal muscle encountered in different experimental studies: (i) increase in the respiration rate per mg of mitochondrial protein at a given ADP concentration as a result of muscle training and decrease in this parameter in hypothyroidism; (ii) asymmetry (different half-transition time, t(1/2)) in phosphocreatine concentration time course between on-transient (rest-->work transition) and off-transient (recovery after exercise); (iii) overshoot in phosphocreatine concentration during recovery after exercise; (iv) variability in the kinetic properties of oxidative phosphorylation in different kinds of muscle under different experimental conditions. No other postulated mechanism is able to explain all these phenomena at the same time and therefore the present paper strongly supports the idea of the parallel activation of ATP usage and different oxidative-phosphorylation complexes during muscle contraction.

Adenosine Diphosphate↗

PubMed2003

Training-induced adaptation of oxidative phosphorylation in skeletal muscles.

Muscle training/conditioning improves the adaptation of oxidative phosphorylation in skeletal muscles to physical exercise. However, the mechanisms underlying this adaptation are still not understood fully. By quantitative analysis of the existing experimental results, we show that training-induced acceleration of oxygen-uptake kinetics at the onset of exercise and improvement of ATP/ADP stability due to physical training are mainly caused by an increase in the amount of mitochondrial proteins and by an intensification of the parallel activation of ATP usage and ATP supply (increase in direct stimulation of oxidative phosphorylation complexes accompanying stimulation of ATP consumption) during exercise.

Adaptation, Physiological↗

PubMed2003

Influence of substrate activation (hydrolysis of ATP by first steps of glycolysis and beta-oxidation) on the effect of enzyme deficiencies, inhibitors, substrate shortage and energy demand on oxidative phosphorylation.

In intact tissues respiratory substrates (glucose, fatty acids) must be activated with the use of ATP before they may be oxidised and used for energy (ATP) production. This activation by product constitutes an example of a typical positive feedback. In the present paper, the influence of substrate activation on the effect of inborn enzyme deficiencies, inhibitors, lowered oxygen tension, respiratory fuel shortage and increased energy demand on respiration and ATP synthesis is studied with the aid of the dynamic computer model of oxidative phosphorylation in isolated mitochondria developed previously. Computer simulations demonstrate that, in the case where oxidative phosphorylation in the whole organism is partially inhibited, the necessity of substrate activation can have significant impact on the relationship between the activity of (particular steps of) oxidative phosphorylation (or the value of energy demand) and the respiration rate. Depending on the sensitivity of ATP usage to ATP concentration, substrate activation may either slightly enhance the effect of the decrease in the oxidative phosphorylation activity (increase in energy demand) or may lead to a non-stability and sudden collapse of the respiration rate and phosphorylation potential below (above) a certain threshold value of oxidative phosphorylation activity (energy demand). This theoretical finding suggests a possible causal relationship between the affinity of ATP usage to [ATP] and the tissue specificity of mitochondrial diseases.

Adenosine Triphosphate↗

PubMed2003

Possible factors determining the non-linearity in the VO2-power output relationship in humans: theoretical studies.

At low power output exercise (below lactate threshold), the oxygen uptake increases linearly with power output, but at high power output exercise (above lactate threshold) some additional oxygen consumption causes a non-linearity in the overall VO(2) (oxygen uptake rate)-power output relationship. The functional significance of this phenomenon for human exercise tolerance is very important, but the mechanisms underlying it remain unknown. In the present work, a computer model of oxidative phosphorylation in intact skeletal muscle developed previously is used to examine the background of this relationship in different modes of exercise. Our simulations demonstrate that the non-linearity in the VO(2)-power output relationship and the difference in the magnitude of this non-linearity between incremental exercise mode and square-wave exercise mode (constant power output exercise) can be generated by introducing into the model some hypothetical factor F (group of associated factors) that accumulate(s) in time during exercise. The performed computer simulations, based on this assumption, give proper time courses of changes in VO(2) and [PCr] after an onset of work of different intensities, including the slow component in VO(2), well matching the experimental results. Moreover, if it is assumed that the exercise terminates because of fatigue when the amount/intensity of F exceed some threshold value, the model allows the generation of a proper shape of the well-known power-duration curve. This fact suggests that the phenomenon of the non-linearity of the VO(2)-power output relationship and the magnitude of this non-linearity in different modes of exercise is determined by some factor(s) responsible for muscle fatigue.

Energy Metabolism↗

PubMed2002

Influence of rapid changes in cytosolic pH on oxidative phosphorylation in skeletal muscle: theoretical studies.

Cytosolic pH in skeletal muscle may vary significantly because of proton production/consumption by creatine kinase and/or proton production by anaerobic glycolysis. A computer model of oxidative phosphorylation in intact skeletal muscle developed previously was used to study the kinetic effect of these variations on the oxidative phosphorylation system. Two kinds of influence were analysed: (i) via the change in pH across the inner mitochondrial membrane and (ii) via the shift in the equilibrium of the creatine kinase-catalysed reaction. Our simulations suggest that cytosolic pH has essentially no impact on the steady-state fluxes and most metabolite concentrations. On the other hand, rapid acidification/alkalization of cytosol causes a transient decrease/increase in the respiration rate. Furthermore, changes in pH seem to affect significantly the kinetic properties of transition between resting state and active state. An increase in pH brought about by proton consumption by creatine kinase at the onset of exercise lengthens the transition time. At intensive exercise levels this pH increase could lead to loss of the stability of the system, if not compensated by glycolytic H+ production. Thus our theoretical results stress the importance of processes/mechanisms that buffer/compensate for changes in cytosolic proton concentration. In particular, we suggest that the second main role of anaerobic glycolysis, apart from additional ATP supply, may be maintaining the stability of the system at intensive exercise.

Adenosine Triphosphate↗

PubMed2002

Parallel activation in the ATP supply-demand system lessens the impact of inborn enzyme deficiencies, inhibitors, poisons or substrate shortage on oxidative phosphorylation in vivo.

A potential kinetic impact of parallel activation of different steps during an increased energy demand on the effect of inborn enzyme deficiencies, physiological inhibitors, external poisons and substrate shortage on oxidative phosphorylation was studied in the theoretical way. Numerical simulations were performed with the aid of the previously developed computer model of oxidative phosphorylation. It was demonstrated that the parallel activation mechanism diminishes significantly changes in fluxes and metabolite concentrations occurring at a given degree of inactivation of the system by one of the above-mentioned factors. It was also shown that parallel activation decreases greatly the threshold value of the relative activity of oxidative phosphorylation, below which the oxygen consumption flux and ATP turnover flux become significantly affected. Finally, computer simulations predicted that parallel activation leads to a considerable increase in the apparent affinity of oxidative phosphorylation to oxygen, which delays the effect of inhibitors and poisons competing with oxygen for the active centre of cytochrome oxidase. It is concluded that one of possible functions of parallel direct activation of different steps of oxidative phosphorylation is to increase the resistance of the system to a decrease in the concentration/activity of different oxidative phosphorylation complexes.

Adenosine Triphosphate↗

PubMed2002

Effect of enzyme deficiencies on oxidative phosphorylation: from isolated mitochondria to intact tissues. Theoretical studies.

The present article briefly summarizes the theoretical studies made by the authors and co-workers on the effect of inborn enzyme deficiencies on oxidative phosphorylation in intact tissues and on the genesis of mitochondrial diseases. The dynamic computer model of oxidative phosphorylation developed previously allowed to extrapolate experimental data (especially: threshold curves describing the dependence of oxygen consumption and ATP turnover on activities/concentrations of particular oxidative phosphorylation enzymes) obtained for isolated muscle mitochondria in state 3 at saturating oxygen concentrations to more physiological conditions prevailing in intact tissues. In particular, theoretical studies demonstrated that the threshold value of the relative activity/concentration of a given mitochondrial complex, below which a significant decrease in the respiration rate takes place, increases with an increase in energy demand. This fact was proposed as a possible explanation of the tissue specificity of mitochondrial diseases. Additionally, a decreased oxygen concentration was shown to increase the threshold value (and flux control coefficient) for cytochrome oxidase. We subsequently developed a model called 'binary mitochondria heteroplasmy', in which there are only two subpopulations of mitochondria: one 'wild-type' and one containing only defected molecules of a given enzyme. In this model we show that a defect has a pronounced effect on oxidative phosphorylation, significantly increasing the threshold value. It was also proposed that a parallel activation in the ATP supply-demand system during an increased energy demand significantly lessens the effect of enzyme deficiencies on oxidative phosphorylation (decreases the threshold value). Finally, the necessity of substrate activation may lead to an instability in the system and to appearance of a second threshold, below which respiration suddenly drops to zero, which is equivalent to the energetic death of a cell.

Adenosine Triphosphate↗