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

2006 ◽  
Vol 291 (6) ◽  
pp. C1213-C1224 ◽  
Author(s):  
Piotr Liguzinski ◽  
Bernard Korzeniewski
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Metabolic Control ◽  
In Silico ◽  
High Energy ◽  
Activation Mechanism ◽  
Atp Production ◽  
Atp Turnover ◽  
Energy Demands

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.

Modeling the effects of hypoxia on ATP turnover in exercising muscle

1992 ◽  
Vol 73 (2) ◽  
pp. 737-742 ◽  
Author(s):  
P. G. Arthur ◽  
M. C. Hogan ◽  
D. E. Bebout ◽  
P. D. Wagner ◽  
P. W. Hochachka
Keyword(s):  
Oxygen Consumption ◽  
Metabolic Control ◽  
Lactate Production ◽  
Atp Synthesis ◽  
Atp Production ◽  
Atp Turnover ◽  
Model Based ◽  
The Face ◽  
Energetic State ◽  
Atp Supply

Most models of metabolic control concentrate on the regulation of ATP production and largely ignore the regulation of ATP demand. We describe a model, based on the results of Hogan et al. (J. Appl. Physiol. 73: 728–736, 1992), that incorporates the effects of ATP demand. The model is developed from the premise that a unique set of intracellular conditions can be measured at each level of ATP turnover and that this relationship is best described by energetic state. Current concepts suggest that cells are capable of maintaining oxygen consumption in the face of declines in the concentration of oxygen through compensatory changes in cellular metabolites. We show that these compensatory changes can cause significant declines in ATP demand and result in a decline in oxygen consumption and ATP turnover. Furthermore we find that hypoxia does not directly affect the rate of anaerobic ATP synthesis and associated lactate production. Rather, lactate production appears to be related to energetic state, whatever the PO2. The model is used to describe the interaction between ATP demand and ATP supply in determining final ATP turnover.

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).

Age-related increase in mitochondrial proton leak and decrease in ATP turnover reactions in mouse hepatocytes

1998 ◽  
Vol 275 (2) ◽  
pp. E197-E206 ◽  
Author(s):  
Mary-Ellen Harper ◽  
Shadi Monemdjou ◽  
Jon J. Ramsey ◽  
Richard Weindruch
Keyword(s):  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Metabolic Control ◽  
Respiratory Control ◽  
Substrate Oxidation ◽  
Membrane Lipid ◽  
Proton Leak ◽  
Control Analysis ◽  
Atp Turnover ◽  
Age Related

Age-related changes in mitochondria, including decreased respiratory control ratios and altered mitochondrial inner membrane lipid composition, led us to study oxidative phosphorylation in hepatocytes from old (30 mo) and young (3 mo) male C57BL/J mice. Top-down metabolic control analysis and its extension, elasticity analysis, were used to identify changes in the control and regulation of the three blocks of reactions constituting the oxidative phosphorylation system: substrate oxidation, mitochondrial proton leak, and the ATP turnover reactions. Resting oxygen consumption of cells from old mice was 15% lower ( P < 0.05) than in young cells. This is explained entirely by a decrease in oxygen consumption supporting ATP turnover reactions. At all values of mitochondrial membrane potential assessed, the proportion of total oxygen consumption used to balance the leak was greater in the old cells than in the young cells. Metabolic control coefficients indicate a shift in control over respiration and phosphorylation away from substrate oxidation toward increased control by leak and by ATP turnover reactions. Control of the actual number of ATP molecules synthesized by mitochondria for each oxygen atom consumed by the ATP turnover and leak reactions was greater in old than in young cells, showing that efficiency in older cells is more sensitive to changes in these two blocks of reactions than in young cells.

Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice

2005 ◽  
Vol 288 (6) ◽  
pp. C1287-C1297 ◽  
Author(s):  
Chad R. Hancock ◽  
Edwin Janssen ◽  
Ronald L. Terjung
Keyword(s):  
Skeletal Muscle ◽  
Adenylate Kinase ◽  
Energy Demand ◽  
Adenine Nucleotide ◽  
Formation Rate ◽  
High Energy ◽  
Energy Demands ◽  
Whole Muscle ◽  
Muscle Contractile ◽  
Contractile Performance

The production of AMP by adenylate kinase (AK) and subsequent deamination by AMP deaminase limits ADP accumulation during conditions of high-energy demand in skeletal muscle. The goal of this study was to investigate the consequences of AK deficiency (−/−) on adenine nucleotide management and whole muscle function at high-energy demands. To do this, we examined isometric tetanic contractile performance of the gastrocnemius-plantaris-soleus (GPS) muscle group in situ in AK1−/− mice and wild-type (WT) controls over a range of contraction frequencies (30–120 tetani/min). We found that AK1−/− muscle exhibited a diminished inosine 5′-monophosphate formation rate (14% of WT) and an inordinate accumulation of ADP (∼1.5 mM) at the highest energy demands, compared with WT controls. AK-deficient muscle exhibited similar initial contractile performance (521 ± 9 and 521 ± 10 g tension in WT and AK1−/− muscle, respectively), followed by a significant slowing of relaxation kinetics at the highest energy demands relative to WT controls. This is consistent with a depressed capacity to sequester calcium in the presence of high ADP. However, the overall pattern of fatigue in AK1−/− mice was similar to WT control muscle. Our findings directly demonstrate the importance of AMP formation and subsequent deamination in limiting ADP accumulation. Whole muscle contractile performance was, however, remarkably tolerant of ADP accumulation markedly in excess of what normally occurs in skeletal muscle.

Effect of hyperthermia and acidosis on equine skeletal muscle mitochondrial oxygen consumption

2020 ◽  
pp. 1-10
Author(s):  
M.S. Davis ◽  
M.R. Fulton ◽  
A. Popken
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Muscle Fatigue ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Complex I ◽  
Mitochondrial Oxygen Consumption ◽  
Biochemical Basis ◽  
Complex Ii

The skeletal muscle of exercising horses develops pronounced hyperthermia and acidosis during strenuous or prolonged exercise, with very high tissue temperature and low pH associated with muscle fatigue or damage. The purpose of this study was to evaluate the individual effects of physiologically relevant hyperthermia and acidosis on equine skeletal muscle mitochondrial function, using ex vivo measurement of oxygen consumption to assess the function of different mitochondrial elements. Fresh triceps muscle biopsies from 6 healthy unfit Thoroughbred geldings were permeabilised to permit diffusion of small molecular weight substrates through the sarcolemma and analysed in a high resolution respirometer at 38, 40, 42, and 44 °C, and pH=7.1, 6.5, and 6.1. Oxygen consumption was measured under conditions of non-phosphorylating (leak) respiration and phosphorylating respiration through Complex I and Complex II. Data were analysed using a one-way repeated measures ANOVA and data are expressed as mean ± standard deviation. Leak respiration was ~3-fold higher at 44 °C compared to 38 °C regardless of electron source (Complex I: 22.88±3.05 vs 8.08±1.92 pmol O2/mg/s), P=0.002; Complex II: 79.14±23.72 vs 21.43±11.08 pmol O2/mg/s, P=0.022), resulting in a decrease in efficiency of oxidative phosphorylation. Acidosis had minimal effect on mitochondrial respiration at pH=6.5, but pH=6.1 resulted in a 50% decrease in mitochondrial oxygen consumption. These results suggest that skeletal muscle hyperthermia decreases the efficiency of oxidative phosphorylation through increased leak respiration, thus providing a specific biochemical basis for hyperthermia-induced muscle fatigue. The effect of myocellular acidosis on mitochondrial respiration was minimal under typical levels of acidosis, but atypically severe acidosis can lead to impairment of mitochondrial function.

Sulphide oxidation and oxidative phosphorylation in the mitochondria of the lugworm

1997 ◽  
Vol 200 (1) ◽  
pp. 83-92 ◽  
Author(s):  
S Vökel ◽  
M K Grieshaber
Keyword(s):  
Oxygen Consumption ◽  
Cytochrome C ◽  
Oxidative Phosphorylation ◽  
Cytochrome C Oxidase ◽  
Electron Flow ◽  
Respiratory Control ◽  
Sulphide Oxidation ◽  
Atp Production ◽  
Sulphide Concentration ◽  
Flow Through

Oxygen consumption, ATP production and cytochrome c oxidase activity of isolated mitochondria from body-wall tissue of Arenicola marina were measured as a function of sulphide concentration, and the effect of inhibitors of the respiratory complexes on these processes was determined. Concentrations of sulphide between 6 and 9 &micro;mol l-1 induced oxygen consumption with a respiratory control ratio of 1.7. Production of ATP was stimulated by the addition of sulphide, reaching a maximal value of 67 nmol min-1 mg-1 protein at a sulphide concentration of 8 &micro;mol l-1. Under these conditions, 1 mole of ATP was formed per mole of sulphide consumed. Higher concentrations of sulphide led to a decrease in ATP production until complete inhibition occurred at approximately 50 &micro;mol l-1. The production of ATP with malate and succinate was stimulated by approximately 15 % in the presence of 4 &micro;mol l-1 sulphide, but decreased at sulphide concentrations higher than 15&shy;20 &micro;mol l-1. Cytochrome c oxidase was also inhibited by sulphide, showing half-maximal inhibition at 1.5 &micro;mol l-1 sulphide. Sulphide-induced ATP production was inhibited by antimycin, cyanide and oligomycin but not by rotenone or salicylhydroxamic acid. The present data indicate that sulphide oxidation is coupled to oxidative phosphorylation solely by electron flow through cytochrome c oxidase, whereas the alternative oxidase does not serve as a coupling site. At sulphide concentrations higher than 20 &micro;mol l-1, oxidation of sulphide serves mainly as a detoxification process rather than as a source of energy.

Ca2+ activation of heart mitochondrial oxidative phosphorylation: role of the F0/F1-ATPase

2000 ◽  
Vol 278 (2) ◽  
pp. C423-C435 ◽  
Author(s):  
Paul R. Territo ◽  
Vamsi K. Mootha ◽  
Stephanie A. French ◽  
Robert S. Balaban
Keyword(s):  
Oxidative Phosphorylation ◽  
Atp Synthesis ◽  
High Energy ◽  
Ruthenium Red ◽  
Maximal Effect ◽  
Production Rates ◽  
Atp Production ◽  
The Matrix

Ca2+ has been postulated as a cytosolic second messenger in the regulation of cardiac oxidative phosphorylation. This hypothesis draws support from the well-known effects of Ca2+ on muscle activity, which is stimulated in parallel with the Ca2+-sensitive dehydrogenases (CaDH). The effects of Ca2+ on oxidative phosphorylation were further investigated in isolated porcine heart mitochondria at the level of metabolic driving force (NADH or Δψ) and ATP production rates (flow). The resulting force-flow (F-F) relationships permitted the analysis of Ca2+ effects on several putative control points within oxidative phosphorylation, simultaneously. The F-F relationships resulting from additions of carbon substrates alone provided a model of pure CaDH activation. Comparing this curve with variable Ca2+ concentration ([Ca2+]) effects revealed an approximate twofold higher ATP production rate than could be explained by a simple increase in NADH or Δψ via CaDH activation. The half-maximal effect of Ca2+ at state 3 was 157 nM and was completely inhibited by ruthenium red (1 μM), indicating matrix dependence of the Ca2+ effect. Arsenate was used as a probe to differentiate between F0/F1-ATPase and adenylate translocase activity by a futile recycling of ADP-arsenate within the matrix, catalyzed by the F0/F1-ATPase. Ca2+increased the ADP arsenylation rate more than twofold, suggesting a direct effect on the F0/F1-ATPase. These results suggest that Ca2+ activates cardiac aerobic respiration at the level of both the CaDH and F0/F1-ATPase. This type of parallel control of both intermediary metabolism and ATP synthesis may provide a mechanism of altering ATP production rates with minimal changes in the high-energy intermediates as observed in vivo.

Contraction Failure of Skeletal Muscle of Rats Recovering from Critical Illness

1997 ◽  
Vol 92 (2) ◽  
pp. 189-195 ◽  
Author(s):  
Olav E. Rooyackers ◽  
Matthijs K. C. Hesselink ◽  
Anton J. M. Wagenmakers
Keyword(s):  
Skeletal Muscle ◽  
Critical Illness ◽  
Muscle Tension ◽  
High Energy ◽  
High Energy Phosphates ◽  
Maximal Aerobic Capacity ◽  
Tension Development ◽  
Atp Production ◽  
Stimulation Period ◽  
Subsequent Loss

1. Most patients recovering from critical illness experience enhanced fatiguability. Previously we have shown that zymosan-induced critical illness in rats is attended by a decreased mitochondrial content (maximal aerobic capacity) in skeletal muscle. We investigated whether this decrease results in an increased reduction in high-energy phosphates and a subsequent loss of contractility during in situ electrical stimulation in rats recovering from zymosan treatment. 2. Plantar-flexor muscles of the hindlimb were electrically stimulated via the innervating nerve to develop maximal isometric tetanic contraction. 3. Decreased concentrations of ATP were measured in gastrocnemius muscle of zymosan-treated rats, both at rest and after stimulation, in comparison with ad libitum-fed and pair-fed control rats. However, no differences in the stimulation-induced decreases in high-energy phosphate levels and changes in other metabolites, except ADP, were observed between the groups. Tension development in the zymosan-treated rats was, however, about 85% less compared with the pair-fed controls during the whole stimulation period. 4. We conclude that the primary cause of the loss of muscle tension in zymosan-treated rats is an insensitivity of skeletal muscle to stimulation via the nerve. An additional derangement in ATP production is, however, indicated by the comparable decreases in energy substrates during development of a dramatically lower tension.

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.

Anaerobic energy release in skeletal muscle during electrical stimulation in men

1987 ◽  
Vol 62 (2) ◽  
pp. 611-615 ◽  
Author(s):  
L. L. Spriet ◽  
K. Soderlund ◽  
M. Bergstrom ◽  
E. Hultman
Keyword(s):  
Skeletal Muscle ◽  
Energy Release ◽  
Contraction Time ◽  
Turnover Rates ◽  
Anaerobic Conditions ◽  
Atp Production ◽  
Atp Turnover ◽  
Anaerobic Energy ◽  
Muscle Biopsies ◽  
Quadriceps Femoris Muscles

The quadriceps femoris muscles of seven men were electrically stimulated under extended anaerobic conditions to quantitate anaerobic energy release and the contribution of the glycolytic system to total ATP production. Muscles were intermittently stimulated 64 times at 20 Hz while leg blood flow was occluded. Each contraction lasted 1.6 s and was followed by 1.6 s of rest. The total contraction time was 102.4 s. Muscle biopsies were taken at rest and following 16, 32, 48, and 64 contractions. The ATP turnover rates during the four 16-contraction periods were 6.12, 2.56, 2.17, and 0.64 mmol X kg dry muscle-1 X s-1 contraction time. Glycolysis provided 58%, phosphocreatine 40% and a decreased ATP store 2% of the consumed energy during the initial 16 contractions. Glycolysis was responsible for 90% of the total ATP production beyond contraction 16. Absolute glycolytic ATP production decreased to 60, 55, and 17% of the amount in the initial 16 contractions during the final three periods, respectively. In conclusion glycolysis produced approximately 195 mmol ATP/kg dry muscle during the initial 48 contractions (76.8 s) and only approximately 15 mmol ATP/kg dry muscle during the final 16 contractions. Equivalent values for total ATP turnover were 278 and 16.5 mmol/kg dry muscle.

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