Interactions of Mitochondrial ATP Synthesis and the Creatine Kinase Equilibrium in Skeletal Muscle

doi:10.1006/jtbi.1994.1184

Journal of Theoretical Biology

Volume 170, Issue 3, 7 October 1994, Pages 239-246

https://doi.org/10.1006/jtbi.1994.1184 Get rights and content

Abstract

In skeletal muscle, creatine kinase imposes constraints on the concentrations of phosphocreatine, creatine, ATP and ADP, which complicate our understanding of the regulation of mitochondrial ATP synthesis, because correlations between oxidation rate (Q) and metabolite concentrations cannot prove causal relations. Two kinds of theory of mitochondrial control in vivo have evolved, based on (i) the hyperbolic relationship between Q and cytosolic [ADP] and (ii) linear correlations between Q and, for example, free energy of ATP hydrolysis. This paper examines some relationships between these theories in order to show (i) to what extent they may be regarded as different expressions of the same metabolic mechanisms, (ii) how they can be understood in terms of general principles of feedback control, and (iii) how they explain relationships between mitochondrial function and resting metabolite concentrations.

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Cited by (37)

Muscle Energetics
2018, Muscle and Exercise Physiology
This chapter summarizes the main processes by which metabolic energy is mobilized to support mechanical work in skeletal muscle. The focus is on processes on the seconds-to-minutes timescale which can be measured noninvasively in vivo by techniques such as magnetic resonance spectroscopy (MRS), yielding quantitative information about cellular metabolism in vivo difficult to obtain in any other way. Muscle energy metabolism can be simplified to a system of ATP supply (oxidative and by anaerobic glycolysis) and demand, buffered by the creatine kinase (CK) reaction. There are important relationships between ATP turnover and cellular pH homeostasis: glycolytic production of lactate is accompanied 1:1 by H⁺, both of which can leave the cell via specialised membrane transporters. ³¹P MRS in particular gives access to some key parts of this system. However, interpretation must take account of the technical characteristics of the methods and their relationship to the underlying biochemistry and physiology.
Dominant and sensitive control of oxidative flux by the ATP-ADP carrier in human skeletal muscle mitochondria: Effect of lysine acetylation
2018, Archives of Biochemistry and Biophysics
Citation Excerpt :
ATP free energy based control models describe the near-linear relationship between oxidative flux and ΔGATP according to non-equilibrium thermodynamics (NET) [4,7,13–15]:v = (ΔΔGATP)(conductance)in which oxidative flux, v, rises linearly according to the product of the fall (“relaxation”) in ATP free energy and a phenomenological proportionality constant, the “conductance” of the oxidative pathway, which also includes the stoichiometry of the transduction [7]. Due to the near equilibrium maintained at CK, at constant pH these two feedback models are fundamentally related to each other [12]. Non-invasive measurement of intact skeletal muscle energy phosphates using 31P-MRS yields estimates of apparent KmADP in the range of 20–40 μM.
The adenine nucleotide translocase (ANT) of the mitochondrial inner membrane exchanges ADP for ATP. Mitochondria were isolated from human vastus lateralis muscle (n = 9). Carboxyatractyloside titration of O₂ consumption rate (J_o) at clamped [ADP] of 21 μM gave ANT abundance of 0.97 ± 0.14 nmol ANT/mg and a flux control coefficient of 82% ± 6%. Flux control fell to 1% ± 1% at saturating (2 mM) [ADP]. The KmADP for J_o was 32.4 ± 1.8 μM. In terms of the free (−3) ADP anion this KmADP was 12.0 ± 0.7 μM. A novel luciferase-based assay for ATP production gave KmADP of 13.1 ± 1.9 μM in the absence of ATP competition. The free anion KmADP in this case was 2.0 ± 0.3 μM. Targeted proteomic analyses showed significant acetylation of ANT Lysine23 and that ANT1 was the most abundant isoform. Acetylation of Lysine23 correlated positively with KmADP, r = 0.74, P = 0.022. The findings underscore the central role played by ANT in the control of oxidative phosphorylation, particularly at the energy phosphate levels associated with low ATP demand. As predicted by molecular dynamic modeling, ANT Lysine23 acetylation decreased the apparent affinity of ADP for ANT binding.
Mitochondria: Investigation of in vivo muscle mitochondrial function by <sup>31</sup>P magnetic resonance spectroscopy
2014, International Journal of Biochemistry and Cell Biology
Citation Excerpt :
The second problem with the interpretation of ST data is that even if VATP did truly represent oxidative ATP synthesis flux, this still could not be taken as a measure of mitochondrial function (Balaban and Koretsky, 2011; Befroy et al., 2012; From and Ugurbil, 2011; Kemp, 2008; Kemp and Brindle, 2012). Mitochondrial ATP synthesis is a demand-driven process regulated by several feedback-loop error signals, such as the concentrations of ADP and Pi (Kemp, 1994; Wu et al., 2007; Jeneson et al., 2009). A decreased net ATP synthesis flux in combination with appropriately decreased error signals would simply represent a lower ATP demand.
The most important function of mitochondria is the production of energy in the form of ATP. The socio-economic impact of human diseases that affect skeletal muscle mitochondrial function is growing, and improving their clinical management critically depends on the development of non-invasive assays to assess mitochondrial function and monitor the effects of interventions. ³¹P magnetic resonance spectroscopy provides two approaches that have been used to assess in vivo ATP synthesis in skeletal muscle: measuring P_i ⟶ ATP exchange flux using saturation transfer in resting muscle, and measuring phosphocreatine recovery kinetics after exercise. However, P_i ⟶ ATP exchange does not represent net mitochondrial ATP synthesis flux and has no simple relationship with mitochondrial function. Post-exercise phosphocreatine recovery kinetics, on the other hand, yield reliable measures of muscle mitochondrial capacity in vivo, whose ability to define the site of functional defects is enhanced by combination with other non-invasive techniques.
Oscillations in energy metabolism
2010, Biochimica et Biophysica Acta - Bioenergetics
Citation Excerpt :
The independency between creatine phosphorylation and muscle mass [51] and exercise intensity [39,52] further evidences that mitochondrial ATP production can be reliably investigated from PCr kinetics. On a theoretical ground, the rate of mitochondrial ATP synthesis would be controlled through a feedback loop involving ADP [39,53,54] as it has been illustrated in isolated mitochondria, animals and humans [50,53,55–60]. Alternatively, it has been proposed that the rate of mitochondrial ATP synthesis could be controlled in a linear manner by the energy released through ATP hydrolysis, ΔGATP[39].
Organisation of mitochondrial metabolism is a quintessential example of a complex dissipative system which can display dynamic instabilities. Several findings have indicated that the conditions inducing instabilities are within the physiological range and that mild perturbations could elicit oscillations. Different mathematical models have been put forth in order to explain the genesis of oscillations in energy metabolism. One model considers mitochondria as an organised network of oscillators and indicates that communication between mitochondria involves mitochondrial reactive oxygen species (ROS) production acting as synchronisers of the energy status of the whole population of mitochondria. An alternative model proposes that extramitochondrial pH variations could lead to mitochondrial oscillations. Oscillatory phenomena in energy metabolism have also been investigated in vivo on the basis of ³¹P magnetic resonance spectroscopy (MRS) measurements of phosphocreatine post-exercise recovery in human and animal skeletal muscle. The corresponding results provide experimental evidences about the role exerted by cytosolic pH on oscillations. Finally a new simple non-linear mathematical model describing the overall chemical reaction of phosphocreatine recovery predicting oscillatory recovery pattern under certain experimental conditions is presented and discussed in the light of the experimental results reported so far.
The mono-exponential pattern of phosphocreatine recovery after muscle exercise is a particular case of a more complex behaviour
2004, Biochimica et Biophysica Acta - Bioenergetics
Citation Excerpt :
There are more complex generalizations of this model, based on non-equilibrium thermodynamics [18,19] resulting in quasi-linear control of respiration rate by cytosolic free energy of ATP hydrolysis [19]. It has been proposed that the two classical models of the respiratory control, kinetic and thermodynamic, may be regarded as different expressions of the same metabolic mechanism [20], and that in skeletal muscle can be both conceivable at different metabolic conditions: equilibrium control being approached at low workloads while kinetic limitations at higher workloads [21]. The pattern of PCr recovery from exercise is reasonably well-described by mono-exponential functions [2–9].
A mathematical model is proposed showing that the mono-exponential recovery of phosphocreatine (PCr) after exercise is an approximation of a more complex pattern, which is identified by a second-order differential equation. The model predicts the possibility of three different patterns of PCr recovery: bi-exponential, oscillatory damped, and critically damped; the mono-exponential pattern being a particular case of the functions which are solutions of the differential equation. The model was tested on a sample of recovery data from 50 volunteers, checking whether the recovery patterns predicted by the model lead to a significant improvement of fit (IF) compared with the mono-exponential pattern. Results show that the IF is linked to pH. Bi-exponential solutions showed an IF in the pH range 6.65–6.85, and the oscillatory solutions at pH>6.9. Critically damped solutions displayed a poor IF. Oscillation frequencies found in the oscillatory recoveries increase at increasing pH. These results show that pH has a pivotal role on the pattern of PCr recovery and implications on the regulation of oxidative phosphorylation are discussed.
Mitochondrial function and oxygen supply in normal and in chronically ischemic muscle: A combined <sup>31</sup>P magnetic resonance spectroscopy and near infrared spectroscopy study in vivo
2001, Journal of Vascular Surgery
Citation Excerpt :
It will be seen (see “Results” section) that this is near unity and also that pH changes (and, therefore, lactate accumulation) are small, which independently suggest34 that the exercise is largely oxidative.7 Oxidative ATP synthesis is a function of three factors: mitochondrial volume and competence, oxygen supply, and the metabolic “driving force” (the change in, eg, ADP concentration33,35). The first two factors can be lumped as the “mitochondrial capacity,” the notional maximum oxidative ATP synthesis rate; in the absence of large pH changes in exercise,36,37 this is conveniently reflected by the postexercise PCr recovery rate constant (0.693/halftime).7,35,38
Purpose: We used ³¹P magnetic resonance spectroscopy (MRS) and near-infrared spectroscopy (NIRS) as a means of quantifying abnormalities in calf muscle oxygenation and adenosine triphosphate (ATP) turnover in peripheral vascular disease (PVD). Methods: Eleven male patients with PVD (mean age, 65 years; range, 55-76 years) and nine male control subjects of similar age were observed in a case-control study in vascular outpatients. Inclusion criteria were more than 6 months' calf claudication (median, 1.5 years; range, 0.6-18 years); proven femoropopliteal or iliofemoral occlusive or stenotic disease; maximum treadmill walking distance (2 km/h, 10° gradient) of 50 to 230 m (mean, 112 m); ankle-brachial pressure index of 0.8 or less during exercise (mean, 0.47; range, 0.29-0.60). Exclusion criteria included diabetes mellitus, anemia, and magnet contraindications. Simultaneous ³¹P MRS and NIRS of lateral gastrocnemius was conducted during 2 to 4 minutes of voluntary 0.5 Hz isometric plantarflexion at 50% and 75% maximum voluntary contraction force (MVC), followed by 5 minutes recovery. Each subject was studied three times, and the results were combined. Results: Compared with control subjects, patients with PVD showed (1) normal muscle cross-sectional area, MVC, ATP turnover, and contractile efficiency (ATP turnover per force/area); (2) larger phosphocreatine (PCr) changes during exercise (ie, increased shortfall of oxidative ATP synthesis) and slower PCr recovery (47% ± 7% [mean ± SEM] decrease in functional capacity for oxidative ATP synthesis, P =.001); (3) faster deoxygenation during exercise and slower postexercise reoxygenation (59% ± 7% decrease in rate constant, P =.0009), despite reduced oxidative ATP synthesis; (4) correlation between PCr and NIRS recovery rate constants (P <.02); and (5) correlations between smaller walking distance, slower PCr recovery, and reduced MVC (P <.001). The precision of the key measurements (rate constants and contractile efficiency) was 12% to 18% interstudy and 30% to 40% intersubject. Conclusion: The primary lesion in oxygen supply dominates muscle metabolism. Reduced force-generation in patients who are affected more may protect muscle from metabolic stress. (J Vasc Surg 2001;34:1103-10.)

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Regular ArticleInteractions of Mitochondrial ATP Synthesis and the Creatine Kinase Equilibrium in Skeletal Muscle

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Regular Article
Interactions of Mitochondrial ATP Synthesis and the Creatine Kinase Equilibrium in Skeletal Muscle