Jerzy A. Zoladz

A model of oxidative phosphorylation in mammalian skeletal muscle

A dynamic computer model of oxidative phosphorylation in oxidative mammalian skeletal muscle was developed. The previously published model of oxidative phosphorylation in isolated skeletal muscle mitochondria was extended by incorporation of the creatine kinase system (creatine kinase plus phosphocreatine/creatine pair), cytosolic proton production/consumption system (proton production/consumption by the creatine kinase-catalysed reaction, efflux/influx of protons), physiological size of the adenine nucleotide pool and some additional minor changes. Theoretical studies performed by means of the extended model demonstrated that the CK system, which allows for large changes in P(i) in relation to isolated mitochondria system, has no significant influence on the kinetic properties of oxidative phosphorylation, as inorganic phosphate only slightly modifies the relationship between the respiration rate and [ADP]. Computer simulations also suggested that the second-order dependence of oxidative phosphorylation on [ADP] proposed in the literature refers only to the ATP synthesis flux, but not to the oxygen consumption flux (the difference between these two fluxes being due to the proton leak). Next, time courses of changes in fluxes and metabolite concentrations during transition between different steady-states were simulated. The model suggests, in accordance with previous theoretical predictions, that activation of oxidative phosphorylation by an increase in [ADP] can (roughly) explain the behaviour of the system only at low work intensities, while at higher work intensities parallel activation of different steps of oxidative phosphorylation is involved.

Skeletal Muscle Fatigue and Decreased Efficiency: Two Sides of the Same Coin?

During high-intensity submaximal exercise, muscle fatigue and decreased efficiency are intertwined closely, and each contributes to exercise intolerance. Fatigue and muscle inefficiency share common mechanisms, for example, decreased “metabolic stability,” muscle metabolite accumulation, decreased free energy of adenosine triphosphate breakdown, limited O2 or substrate availability, increased glycolysis, pH disturbance, increased muscle temperature, reactive oxygen species production, and altered motor unit recruitment patterns.

Oxygen uptake does not increase linearly at high power outputs during incremental exercise test in humans

Abstract A group of 12 healthy non-smoking men [mean age 22.3 (SD 1.1) years], performed an incremental exercise test. The test started at 30 W, followed by increases in power output (P) of 30 W every 3 min, until exhaustion. Blood samples were taken from an antecubital vein for determination of plasma concentration lactate [La−]pl and acid-base balance variables. Below the lactate threshold (LT) defined in this study as the highest P above which a sustained increase in [La−]pl was observed (at least 0.5 mmol · l−1 within 3 min), the pulmonary oxygen uptake (V˙O2) measured breath-by-breath, showed a linear relationship with P. However, at P above LT [in this study 135 (SD 30) W] there was an additional accumulating increase in V˙O2 above that expected from the increase in P alone. The magnitude of this effect was illustrated by the difference in the final P observed at maximal oxygen uptake (V˙O2max) during the incremental exercise test (Pmax,obs at V˙O2max) and the expected power output at V˙O2max(Pmax,exp at V˙O2max) predicted from the linear V˙O2-P relationship derived from the data collected below LT. The Pmax,obs at V˙O2max amounting to 270 (SD 19) W was 65.1 (SD 35) W (19%) lower (P<0.01) than the Pmax,exp at V˙O2max. The mean value of V˙O2max reached at Pmax,obs amounted to 3555 (SD 226) ml · min−1 which was 572 (SD 269) ml · min−1 higher (P<0.01) than the V˙O2 expected at this P, calculated from the linear relationship between V˙O2 and P derived from the data collected below LT. This fall in locomotory efficiency expressed by the additional increase in V˙O2, amounting to 572 (SD 269) ml O2 · min−1, was accompanied by a significant increase in [La−]pl amounting to 7.04 (SD 2.2) mmol · l−1, a significant increase in blood hydrogen ion concentration ([H+]b) to 7.4 (SD 3) nmol · l−1 and a significant fall in blood bicarbonate concentration to 5.78 (SD 1.7) mmol · l−1, in relation to the values measured at the P of the LT. We also correlated the individual values of the additional V˙O2 with the increases (Δ) in variables [La−]pl and Δ[H+]b. The Δ values for [La−]pl and Δ[H+]b were expressed as the differences between values reached at the Pmax,obs at V˙O2max and the values at LT. No significant correlations between the additional V˙O2 and Δ[La−]pl on [H+]b were found. In conclusion, when performing an incremental exercise test, exceeding P corresponding to LT was accompanied by a significant additional increase in V˙O2 above that expected from the linear relationship between V˙O2 and P occurring at lower P. However, the magnitude of the additional increase in V˙O2 did not correlate with the magnitude of the increases in [La−]pl and [H+]b reached in the final stages of the incremental test.

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.

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.

Human Muscle Power Generating Capability During Cycling at Different Pedalling Rates

The effect of different pedalling rates (40, 60, 80, 100 and 120 rev min−1) on power generating capability, oxygen uptake (V̇O2) and blood lactate concentration [La]b during incremental tests was studied in seven subjects. No significant differences in V̇O2,max were found (mean ± S.D., 5.31 ± 0.13 l min−1). The final external power output delivered to the ergometer during incremental tests (PI,max) was not significantly different when cycling at 60, 80 or 100 rev min−1 (366 ± 5 W). A significant decrease in PI,max of ∼60 W was observed at 40 and 120 rev min−1 compared with 60 and 100 rev min−1, respectively (P < 0.01). At 120 rev min−1 there was also a pronounced upward shift of the V̇O2‐power output (V̇O2‐P) relationship. At 50 W δV̇O2 between 80 and 100 rev min−1 amounted to +0.43 l min−1 but to +0.87 l min−1 between 100 and 120 rev min−1. The power output corresponding to 2 and 4 mmol l−1 blood lactate concentration (P[La]2 and P[La]4) was also significantly lower (> 50 W) at 120 rev min−1 (P < 0.01) while pedalling at 40, 60, 80 and 100 rev min−1 showed no significant difference. The maximal peak power output (PM,max) during 10 s sprints increased with pedalling rate up to 100 rev min−1. Our study indicates that with increasing pedalling rate the reserves in power generating capability increase, as illustrated by the PI,max/PM,max ratio (54.8, 44.8, 38.1, 34.6, 29.2%), the P[La]4/PM,max ratio (50.4, 38.9, 31.0, 27.7, 22.9%) and the P[La]2/PM,max ratio (42.8, 33.5, 25.6, 23.1, 15.6%) increases. Taking into consideration the V̇O2,max, the PI,max and the reserve in power generating capability we concluded that choosing a high pedalling rate when performing high intensity cycling exercise may be beneficial since it provides greater reserve in power generating capability and this may be advantageous to the muscle in terms of resisting fatigue. However, beyond 100 rev min−1 there is a decrease in external power that can be delivered for an given V̇O2 with an associated earlier onset of metabolic acidosis and clearly this will be disadvantageous for sustained high intensity exercise.

Training‐induced acceleration of O2 uptake on‐kinetics precedes muscle mitochondrial biogenesis in humans

•  What is the central question of this study? A few weeks of endurance training accelerate the oxygen uptake () on‐kinetics in humans. The main aim of the present study was to determine whether the acceleration of on‐kinetics obtained by a short period of moderate‐intensity training can be explained by an intensification of mitochondrial biogenesis. •  What is the main finding and its importance? We demonstrated that 5 weeks of moderate‐intensity training accelerates the on‐kinetics during moderate‐intensity cycling in the absence of enhanced mitochondrial biogenesis or capillarization in the trained muscles. We postulate that in the early stages of training an intensification of ‘parallel activation’ of oxidative phosphorylation could account for the shortening of the on‐transient.

Slow \dot{V}{\text{O}}_{2} kinetics during moderate-intensity exercise as markers of lower metabolic stability and lower exercise tolerance

An analysis of previously published data obtained by our group on patients characterized by markedly slower pulmonary

Detection of the change point in oxygen uptake during an incremental exercise test using recursive residuals: relationship to the plasma lactate accumulation and blood acid base balance

\dot{V}{\text{O}}_{2}