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

2002 ◽  
Vol 365 (1) ◽  
pp. 249-258 ◽  
Author(s):  
Bernard KORZENIEWSKI ◽  
Jerzy A. ZOLADZ
Keyword(s):  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Oxidative Phosphorylation ◽  
Kinetic Properties ◽  
Main Role ◽  
Anaerobic Glycolysis ◽  
Cytosolic Ph ◽  
Intensive Exercise ◽  
Proton Production ◽  
The Stability

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.

scholarly journals Regulation of oxidative phosphorylation in different muscles and various experimental conditions

2003 ◽  
Vol 375 (3) ◽  
pp. 799-804 ◽  
Author(s):  
Bernard KORZENIEWSKI
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Muscle Contraction ◽  
Mitochondrial Protein ◽  
Experimental Studies ◽  
Kinetic Properties ◽  
Protonmotive Force ◽  
Experimental Conditions ◽  
Parallel Activation ◽  
Stimulation Of

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, t1/2) 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.

scholarly journals Faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart related to cytosolic inorganic phosphate (Pi) accumulation

2016 ◽  
Vol 121 (2) ◽  
pp. 424-437 ◽  
Author(s):  
Bernard Korzeniewski
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Inorganic Phosphate ◽  
Mitochondrial Diseases ◽  
Healthy Tissue ◽  
Force Generation ◽  
Kinetic Properties ◽  
Moderate Exercise ◽  
Work Transition

A model of the cell bioenergetic system was used to compare the effect of oxidative phosphorylation (OXPHOS) deficiencies in a broad range of moderate ATP demand in skeletal muscle and heart. Computer simulations revealed that kinetic properties of the system are similar in both cases despite the much higher mitochondria content and “basic” OXPHOS activity in heart than in skeletal muscle, because of a much higher each-step activation (ESA) of OXPHOS in skeletal muscle than in heart. Large OXPHOS deficiencies lead in both tissues to a significant decrease in oxygen consumption (V̇o2) and phosphocreatine (PCr) and increase in cytosolic ADP, Pi, and H+. The main difference between skeletal muscle and heart is a much higher cytosolic Pi concentration in healthy tissue and much higher cytosolic Pi accumulation (level) at low OXPHOS activities in the former, caused by a higher PCr level in healthy tissue (and higher total phosphate pool) and smaller Pi redistribution between cytosol and mitochondria at OXPHOS deficiency. This difference does not depend on ATP demand in a broad range. A much greater Pi increase and PCr decrease during rest-to-moderate work transition in skeletal muscle at OXPHOS deficiencies than at normal OXPHOS activity significantly slows down the V̇o2 on-kinetics. Because high cytosolic Pi concentrations cause fatigue in skeletal muscle and can compromise force generation in skeletal muscle and heart, this system property can contribute to the faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart. Shortly, skeletal muscle with large OXPHOS deficiencies becomes fatigued already during low/moderate exercise.

Mechanisms of the effect of oxidative phosphorylation deficiencies on the skeletal muscle bioenergetic system in patients with mitochondrial myopathies

2021 ◽  
Author(s):  
Bernard Korzeniewski
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Muscle Fatigue ◽  
Exercise Intolerance ◽  
Kinetic Properties ◽  
Work Intensity ◽  
Mitochondrial Myopathies ◽  
Threshold Mechanism ◽  
Kinetic Effects ◽  
Double Threshold

Simulations carried out using a previously-developed model of the skeletal muscle bioenergetic system, involving the "Pi double-threshold" mechanism of muscle fatigue, lead to the conclusion that a decrease in the oxidative phosphorylation (OXPHOS) activity, caused by mutations in mitochondrial or nuclear DNA, is the main mechanism underlying the changes in the kinetic properties of the system in mitochondrial myopathies (MM). These changes generally involve the very-heavy-exercise-like behavior and exercise termination because of fatigue at low work intensities. In particular, a sufficiently large (at a given work intensity) decrease in OXPHOS activity leads to slowing of the primary phase II of the V̇O2 on-kinetics, decrease in V̇O2max, appearance of the slow component of the V̇O2 on-kinetics, exercise intolerance and lactic acidosis at relatively low power outputs encountered in experimental studies in MM patients. Thus, the "Pi double-threshold" mechanism of muscle fatigue is able to account, at least semi-quantitatively, for various kinetic effects of inborn OXPHOS deficiencies of the skeletal muscle bioenergetic system. Exercise can be potentially lengthened and V̇O2max elevated in MM patients through an increase in peak Pi (Pipeak), at which exercise is terminated because of fatigue. Generally, a mechanism underlying the kinetic effects of OXPHOS deficiencies on the skeletal muscle bioenergetic system in MM is proposed that was absent in the literature.

scholarly journals Possible mechanisms underlying slow component of V̇o2 on-kinetics in skeletal muscle

2015 ◽  
Vol 118 (10) ◽  
pp. 1240-1249 ◽  
Author(s):  
Bernard Korzeniewski ◽  
Jerzy A. Zoladz
Keyword(s):  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Gradual Increase ◽  
Slow Component ◽  
Anaerobic Glycolysis ◽  
Atp Production ◽  
Slow Decrease ◽  
Muscle Ph ◽  
Creatine Kinase Reaction ◽  
Atp Supply

A computer model of a skeletal muscle bioenergetic system is used to study the background of the slow component of oxygen consumption V̇o2 on-kinetics in skeletal muscle. Two possible mechanisms are analyzed: inhibition of ATP production by anaerobic glycolysis by progressive cytosol acidification (together with a slow decrease in ATP supply by creatine kinase) and gradual increase of ATP usage during exercise of constant power output. It is demonstrated that the former novel mechanism is potent to generate the slow component. The latter mechanism further increases the size of the slow component; it also moderately decreases metabolite stability and has a small impact on muscle pH. An increase in anaerobic glycolysis intensity increases the slow component, elevates cytosol acidification during exercise, and decreases phosphocreatine and Pi stability, although slightly increases ADP stability. A decrease in the P/O ratio (ATP molecules/O2 molecules) during exercise cannot also be excluded as a relevant mechanism, although this issue requires further study. It is postulated that both the progressive inhibition of anaerobic glycolysis by accumulating protons (together with a slow decrease of the net creatine kinase reaction rate) and gradual increase of ATP usage during exercise, and perhaps a decrease in P/O, contribute to the generation of the slow component of the V̇o2 on-kinetics in skeletal muscle.

scholarly journals Alterations of skeletal muscle bioenergetics in a mouse with F508del mutation leading to a cystic fibrosis-like condition

2019 ◽  
Vol 317 (2) ◽  
pp. E327-E336
Author(s):  
Nicola Lai ◽  
Chinna Kummitha ◽  
Mitchell Drumm ◽  
Charles Hoppel
Keyword(s):  
Skeletal Muscle ◽  
Cystic Fibrosis ◽  
Creatine Kinase ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Aerobic Capacity ◽  
Electron Transport Chain ◽  
Kinase Activity ◽  
Creatine Kinase Activity ◽  
Transport Chain

High energy expenditure is reported in cystic fibrosis (CF) animal models and patients. Alterations in skeletal muscle oxidative capacity, fuel utilization, and the creatine kinase-phosphocreatine system suggest mitochondrial dysfunction. Studies were performed on congenic C57BL/6J and F508del ( Cftrtm1kth) mice. Indirect calorimetry was used to measure gas exchange to evaluate aerobic capacity during treadmill exercise. The bioenergetic function of skeletal muscle subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) was evaluated using an integrated approach combining measurement of the rate of oxidative phosphorylation by polarography and of electron transport chain activities by spectrophotometry. CF mice have reduced maximal aerobic capacity. In SSM of these mice, oxidative phosphorylation was impaired in the presence of complex I, II, III, and IV substrates except when glutamate was used as substrate. This impairment appeared to be caused by a defect in complex V activity, whereas the oxidative system of the electron transport chain was unchanged. In IFM, oxidative phosphorylation and electron transport chain activities were preserved, whereas complex V activity was reduced, in CF. Furthermore, creatine kinase activity was reduced in both SSM and IFM of CF skeletal muscle. The decreased complex V activity in SSM resulted in reduced oxidative phosphorylation, which could explain the reduced skeletal muscle response to exercise in CF mice. The decrease in mitochondrial creatine kinase activity also contributed to this poor exercise response.

Age-related changes in ATP-producing pathways in human skeletal muscle in vivo

2005 ◽  
Vol 99 (5) ◽  
pp. 1736-1744 ◽  
Author(s):  
Ian R. Lanza ◽  
Douglas E. Befroy ◽  
Jane A. Kent-Braun
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Atp Synthesis ◽  
Older Men ◽  
Oxidative Capacity ◽  
Glycolytic Flux ◽  
Synthesis Rate ◽  
Anaerobic Glycolysis ◽  
Atp Production ◽  
Age Related

Energy for muscle contractions is supplied by ATP generated from 1) the net hydrolysis of phosphocreatine (PCr) through the creatine kinase reaction, 2) oxidative phosphorylation, and 3) anaerobic glycolysis. The effect of old age on these pathways is unclear. The purpose of this study was to examine whether age may affect ATP synthesis rates from these pathways during maximal voluntary isometric contractions (MVIC). Phosphorus magnetic resonance spectroscopy was used to assess high-energy phosphate metabolite concentrations in skeletal muscle of eight young (20–35 yr) and eight older (65–80 yr) men. Oxidative capacity was assessed from PCr recovery after a 16-s MVIC. We determined the contribution of each pathway to total ATP synthesis during a 60-s MVIC. Oxidative capacity was similar across age groups. Similar rates of ATP synthesis from PCr hydrolysis and oxidative phosphorylation were observed in young and older men during the 60-s MVIC. Glycolytic flux was higher in young than older men during the 60-s contraction ( P < 0.001). When expressed relative to the overall ATP synthesis rate, older men relied on oxidative phosphorylation more than young men ( P = 0.014) and derived a smaller proportion of ATP from anaerobic glycolysis ( P < 0.001). These data demonstrate that although oxidative capacity was unaltered with age, peak glycolytic flux and overall ATP production from anaerobic glycolysis were lower in older men during a high-intensity contraction. Whether this represents an age-related limitation in glycolytic metabolism or a preferential reliance on oxidative ATP production remains to be determined.

Regulation of oxidative phosphorylation during work transitions results from its kinetic properties

2014 ◽  
Vol 116 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Bernard Korzeniewski
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Metabolic Control ◽  
Experimental Studies ◽  
Complex Iii ◽  
Activation Mechanism ◽  
Kinetic Properties ◽  
Group Model ◽  
Work Transitions

The regulation of oxidative phosphorylation (OXPHOS) during work transitions in skeletal muscle and heart is still not well understood. Different computer models of this process have been developed that are characterized by various kinetic properties. In the present research-polemic theoretical study it is argued that models belonging to one group (Model A), which predict that among OXPHOS complexes complex III keeps almost all of the metabolic control over oxygen consumption (Vo2) and involve a strong complex III activation by inorganic phosphate (Pi), lead to the conclusion that an increase in Pi is the main mechanism responsible for OXPHOS activation (feedback-activation mechanism). Models belonging to another group (Model B), which were developed to take into account an approximately uniform distribution of metabolic control over Vo2 among particular OXPHOS complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, phosphate carrier) encountered in experimental studies in isolated mitochondria, predict that all OXPHOS complexes are directly activated in parallel with ATP usage and NADH supply by some external cytosolic factor/mechanism during rest-to-work or low-to-high work transitions in skeletal muscle and heart (“each-step-activation” mechanism). Model B demonstrates that different intensities of each-step activation can account for the very different (slopes of) phenomenological Vo2-ADP relationships observed in various skeletal muscles and heart. Thus they are able to explain the differences in the regulation of OXPHOS during work transitions between skeletal muscle (where moderate changes in ADP take place) and intact heart in vivo (where ADP is essentially constant).

Modulation of ATP production by oxygen in obstructive lung disease as assessed by 31P-MRS

1995 ◽  
Vol 78 (6) ◽  
pp. 2218-2227 ◽  
Author(s):  
E. T. Mannix ◽  
M. D. Boska ◽  
P. Galassetti ◽  
G. Burton ◽  
F. Manfredi ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Oxidative Phosphorylation ◽  
Oxidative Metabolism ◽  
Chronic Obstructive ◽  
Resonance Spectroscopy ◽  
Anaerobic Glycolysis ◽  
Atp Production ◽  
Copd Patients ◽  
Group 2 ◽  
Group 1

Inadequate O2 supply may impair intramuscular oxidative metabolism and O2 availability may modulate ATP production within exercising muscle. Therefore, we studied ATP flux from anaerobic glycolysis, the creatine kinase reaction, and oxidative phosphorylation using 31P-magnetic resonance spectroscopy kinetic data collected during exercise. We examined six chronic obstructive pulmonary disease (COPD) patients with severe hypoxemia (group 1), seven COPD patients with mild hypoxemia (group 2), and seven healthy control subjects. Exercise (90-s isometric contraction of the gastrocnemius-soleus muscle group, 40% of max) was performed on room air for all subjects; for COPD patients, it was repeated during supplemental O2 at identical power outputs, with 60-min rest between the two sets. In group 1 (air vs. O2), oxidative phosphorylation ATP production was lower (P < 0.05), anaerobic glycolysis ATP production was higher (P < 0.05), and anaerobic glycolysis plus creatine kinase ATP production tended to be higher (P = 0.06). In group 2, no differences were observed across conditions. Assuming that mitochondrial size, density, function, and redox state were not affected by acute changes in the inspired O2 fraction, reduced O2 availability is the remaining factor that could have limited oxidative ATP production during hypoxemia. In conclusion, in severely hypoxemic COPD patients, O2 availability apparently limits intramuscular oxidative metabolism because acute hypoxemia increases anaerobic and decreases aerobic ATP production.

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