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.

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.

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.

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.

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 The Effect of Inorganic Phosphate on Force Generation in Single Myofibrils from Rabbit Skeletal Muscle

2000 ◽  
Vol 78 (6) ◽  
pp. 3081-3092 ◽  
Author(s):  
C. Tesi ◽  
F. Colomo ◽  
S. Nencini ◽  
N. Piroddi ◽  
C. Poggesi
Keyword(s):  
Skeletal Muscle ◽  
Inorganic Phosphate ◽  
Rabbit Skeletal Muscle ◽  
Force Generation

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).

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.

scholarly journals Mitochondrial oxygen consumption in early postmortem permeabilized skeletal muscle fibers is influenced by cattle breed

2020 ◽  
Vol 98 (3) ◽  
Author(s):  
Patricia M Ramos ◽  
Chengcheng Li ◽  
Mauricio A Elzo ◽  
Stephanie E Wohlgemuth ◽  
Tracy L Scheffler
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Heat Tolerance ◽  
Complex I ◽  
Citrate Synthase ◽  
Ex Vivo ◽  
Muscle Fibers ◽  
Cattle Breed ◽  
Early Postmortem

Abstract Functional properties and integrity of skeletal muscle mitochondria (mt) during the early postmortem period may influence energy metabolism and pH decline, thereby impacting meat quality development. Angus typically produce more tender beef than Brahman, a Bos indicus breed known for heat tolerance. Thus, our objectives were to compare mt respiratory function in muscle collected early postmortem (1 h) from Angus and Brahman steers (n = 26); and to evaluate the effect of normal and elevated temperature on mt function ex vivo. We measured mt oxygen consumption rate (OCR) in fresh-permeabilized muscle fibers from Longissimus lumborum (LL) at 2 temperatures (38.5 and 40.0 °C) and determined citrate synthase (CS) activity and expression of several mt proteins. The main effects of breed, temperature, and their interaction were tested for mt respiration, and breed effect was tested for CS activity and protein expression. Breed, but not temperature (P > 0.40), influenced mt OCR (per tissue weight), with Brahman exhibiting greater complex I+II-mediated oxidative phosphorylation capacity (P = 0.05). Complex I- and complex II-mediated OCR also tended to be greater in Brahman (P = 0.07 and P = 0.09, respectively). Activity of CS was higher in LL from Brahman compared to Angus (P = 0.05). Expression of specific mt proteins did not differ between breeds, except for higher expression of adenosine triphosphate (ATP) synthase subunit 5 alpha in Brahman muscle (P = 0.04). Coupling control ratio differed between breeds (P = 0.05), revealing greater coupling between oxygen consumption and phosphorylation in Brahman. Our data demonstrate that both Angus and Brahman mt retained functional capacity and integrity 1-h postmortem; greater oxidative phosphorylation capacity and coupling in Brahman mt could be related to heat tolerance and impact early postmortem metabolism.

scholarly journals Regulation of metabolism: the rest-to-work transition in skeletal muscle

2015 ◽  
Vol 309 (9) ◽  
pp. E793-E801 ◽  
Author(s):  
David F. Wilson
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Atp Synthesis ◽  
Creatine Phosphate ◽  
Valuable Insight ◽  
Metabolic Homeostasis ◽  
Lag Period ◽  
Metabolic Behavior

Mitochondrial oxidative phosphorylation is programmed to set and maintain metabolic homeostasis, and understanding that program is essential for an integrated view of cellular and tissue metabolism. The behavior predicted by a mechanism-based model for oxidative phosphorylation is compared with that experimentally measured for skeletal muscle when work is initiated. For the model, initiation of work is simulated by imposing a rate of ATP utilization of either 0.6 (equivalent of 13.4 ml O2·100 g tissue−1·min−1 or 6 μmol O2·g tissue−1·min−1) or 0.3 mM ATP/s. Creatine phosphate ([CrP]) decrease, both experimentally measured and predicted by the model, can be fit to a single exponential. Increase in ATP synthesis begins immediately but can show a “lag period,” during which the rate accelerates. The length of the lag period is similar for both experiment and model; in the model, the lag depends on intramitochondrial [NAD+]/[NADH], mitochondrial content, and size of the creatine pool ([CrP] + [Cr]) as well as the resting [CrP]/[Cr]. For in vivo conditions, increase in oxygen consumption may be linearly correlated with a decrease in [CrP] and an increase in inorganic phosphate ([Pi]) and [Cr]. The decrease in [CrP], resting and working steady state [CrP], and the increase in oxygen consumption are dependent on the Po2 in the inspired gas (experimental) or tissue Po2 (model). The metabolic behavior predicted by the model is consistent with available experimental measurements in muscle upon initiation of work, with the model providing valuable insight into how metabolic homeostasis is set and maintained.

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