scholarly journals A metabolic control analysis of kinetic controls in ATP free energy metabolism in contracting skeletal muscle

2000 ◽  
Vol 279 (3) ◽  
pp. C813-C832 ◽  
Author(s):  
J. A. L. Jeneson ◽  
H. V. Westerhoff ◽  
M. J. Kushmerick
Keyword(s):  
Skeletal Muscle ◽  
Free Energy ◽  
Steady State ◽  
Energy Metabolism ◽  
Metabolic Control ◽  
Kinetic Control ◽  
Control Analysis ◽  
Flexor Muscle ◽  
Metabolic Control Theory ◽  
Forearm Flexor

A system analysis of ATP free energy metabolism in skeletal muscle was made using the principles of metabolic control theory. We developed a network model of ATP free energy metabolism in muscle consisting of actomyosin ATPase, sarcoplasmic reticulum (SR) Ca2+-ATPase, and mitochondria. These components were sufficient to capture the major aspects of the regulation of the cytosolic ATP-to-ADP concentration ratio (ATP/ADP) in muscle contraction and had inherent homeostatic properties regulating this free energy potential. As input for the analysis, we used ATP metabolic flux and the cytosolic ATP/ADP at steady state at six contraction frequencies between 0 and 2 Hz measured in human forearm flexor muscle by 31P-NMR spectroscopy. We used the mathematical formalism of metabolic control theory to analyze the distribution of fractional kinetic control of ATPase flux and the ATP/ADP in the network at steady state among the components over this experimental range and an extrapolated range of stimulation frequencies (up to 10 Hz). The control analysis showed that the contractile actomyosin ATPase has dominant kinetic control of ATP flux in forearm flexor muscle over the 0- to 1.6-Hz range of contraction frequencies that resulted in steady states, as determined by 31P-NMR. However, flux control begins to shift toward mitochondria at >1 Hz. This inversion of flux control from ATP demand to ATP supply control hierarchy progressed as the contraction frequency increased past 2 Hz and was nearly complete at 10 Hz. The functional significance of this result is that, at steady state, ATP free energy consumption cannot outstrip the ATP free energy supply. Therefore, this reduced, three-component muscle ATPase system is inherently homeostatic.

Metabolic control analysis of insulin-stimulated glucose disposal in rat skeletal muscle

1999 ◽  
Vol 277 (3) ◽  
pp. E505-E512 ◽  
Author(s):  
Beat M. Jucker ◽  
Nicole Barucci ◽  
Gerald I. Shulman
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Control ◽  
Glucose Transport ◽  
Distributed Control ◽  
Metabolic Flux ◽  
Glycogen Synthesis ◽  
Metabolic Control Analysis ◽  
Glucose Disposal ◽  
Control Analysis ◽  
Awake Rats

Metabolic control analysis was used to calculate the distributed control of insulin-stimulated skeletal muscle glucose disposal in awake rats. Three separate hyperinsulinemic infusion protocols were performed: 1) protocol I was a euglycemic (∼6 mM)-hyperinsulinemic (10 mU ⋅ kg−1 ⋅ min−1) clamp, 2) protocol II was a hyperglycemic (∼11 mM)-hyperinsulinemic (10 mU ⋅ kg−1 ⋅ min−1) clamp, and 3) protocol III was a euglycemic (∼6 mM)-hyperinsulinemic (10 mU ⋅ kg−1 ⋅ min−1)-lipid/heparin (increased plasma free fatty acid) clamp. [1-13C]glucose was administered in all three protocols for a 3-h period, during which time [1-13C]glucose label incorporation into [1-13C]glycogen, [3-13C]lactate, and [3-13C]alanine was detected in the hindlimb of awake rats via13C-NMR. Combined steady-state and kinetic data were used to calculate rates of glycogen synthesis and glycolysis. Additionally, glucose 6-phosphate (G-6- P) was measured in the hindlimb muscles with the use of in vivo31P-NMR during the three infusion protocols. The clamped glucose infusion rates were 31.6 ± 2.9, 49.7 ± 1.0, and 24.0 ± 1.5 mg ⋅ kg−1 ⋅ min−1at 120 min in protocols I– III, respectively. Rates of glycolysis were 62.1 ± 10.3, 71.6 ± 11.8, and 19.5 ± 3.6 nmol ⋅ g−1 ⋅ min−1and rates of glycogen synthesis were 125 ± 15, 224 ± 23, and 104 ± 17 nmol ⋅ g−1 ⋅ min−1in protocols I– III, respectively. Insulin-stimulated G-6- Pconcentrations were 217 ± 8, 265 ± 12, and 251 ± 9 nmol/g in protocols I– III, respectively. A top-down approach to metabolic control analysis was used to calculate the distributed control among glucose transport/phosphorylation [GLUT-4/hexokinase (HK)], glycogen synthesis, and glycolysis from the metabolic flux and G-6- P data. The calculated values for the control coefficients ( C) of these three metabolic steps ([Formula: see text]= 0.55 ± 0.10,[Formula: see text]= 0.30 ± 0.06, and[Formula: see text] = 0.15 ± 0.02; where J is glucose disposal flux, and glycogen syn is glycogen synthesis) indicate that there is shared control of glucose disposal and that glucose transport/phosphorylation is responsible for the majority of control of insulin-stimulated glucose disposal in skeletal muscle.

scholarly journals Glucose and the ATP paradox in yeast

2000 ◽  
Vol 352 (2) ◽  
pp. 593-599 ◽  
Author(s):  
Oscar J. G. SOMSEN ◽  
Martijn A. HOEBEN ◽  
Eugenia ESGALHADO ◽  
Jacky L. SNOEP ◽  
Diana VISSER ◽  
...  
Keyword(s):  
Free Energy ◽  
Numerical Simulations ◽  
Metabolic Control ◽  
Metabolic Control Analysis ◽  
Yeast Cells ◽  
Control Analysis ◽  
Aerobic Growth ◽  
Glucose Limitation ◽  
Atp Concentration ◽  
Carbon Substrates

A sustained decrease in the intracellular ATP concentration has been observed when extra glucose was added to yeast cells growing aerobically under glucose limitation. Because glucose degradation is the main source of ATP-derived free energy, this is a counter-intuitive phenomenon, which cannot be attributed to transient ATP consumption in the initial steps of glycolysis. We present a core model for aerobic growth in which glucose supplies carbon, as well as free energy, for biosynthesis. With Metabolic Control Analysis and numerical simulations, we demonstrate that the decrease in the ATP concentration can be reproduced if the biosynthetic route is more strongly activated by carbon substrates than is the catabolic (ATP-producing) route.

scholarly journals Improved Synthesis of Flavonoids by Simulation of Nargenine Chalcone Biosynthetic Reaction

2020 ◽  
pp. 61-80
Author(s):  
Mamta Sagar ◽  
Pramod Wasudev Ramteke ◽  
Ravindra Nath Katiyar ◽  
Shameem Ahmad
Keyword(s):  
Steady State ◽  
Metabolic Control ◽  
Chalcone Synthase ◽  
Phenylpropanoid Pathway ◽  
Metabolic Control Analysis ◽  
Flavonoid Biosynthesis ◽  
Control Analysis ◽  
Initial Concentration ◽  
Product Specificity ◽  
Malonyl Coa

Metabolic Control Analysis provides a quantitative description of concentration dynamics with the change in system parameters. A metabolic Control Analysis aids determination of the threshold value of metabolites involved in a reaction and also helps to understand the role of various parameters in a reaction. In this work, a metabolic model of a Naringenine chalcone biosynthetic reaction is defined and a time series simulation was carried out based on the law of Mass action. Initial concentration of p-Coumaroyl-CoA and Malonyl-CoA were taken 5.0*10-2 mM 2.2*10-3 mM respectively. This concentration was then simulated over time for 10 seconds to find the steady state. Final concentration of  Naringenine chalcone,CO2, and CoA becomes 8.593946e-004 mM after 5.00 second of simulation at reaction constant 6.587753e-005 mM*ml/s. Steady state solution shows that Initial concentration of Naringenine chalcone was 2.199777e-003 mM which is eventually converted into 2.785128e+013 seconds half-life concentration of product at 7.898e-017 mM/s rate and  0.000000e+000 mM*ml/s  rate constant. Phenylpropanoid pathway was analysed to predict all the enzymes that can maximise and minimise the concentration of  Malonyl-CoA and P-Coumaroyl-CoA which leads to flavonoid biosynthesis. In the Phenylpropanoid pathway four enzymes Phenylalanine/tyrosine ammonia lyase, trans-cinnamate 4-monooxygenase, Phenylalanine ammonia lyase, maximise the flavonoid biosynthesis. This analysis shows that other enzymes minimise the concentrations of  Malonyl-CoA and P-coumaroyl-CoA, these are Cinnamoyl Co A reductase, shikimate O hydroxyl transferase HCT), Oxidoreductase. Furthermore, Protein domain analysis of chalcone synthase mutants ( 1jwx Medicago sativa and 4yjy from Oryza sativa) was done to predict structural features to understand reaction mechanism and structure-based engineering to maximise flavonoid biosynthesis. Natural sequence variation CHS G256A, G256V, G256L, and G256F mutants of residue 256 reduce the size of the active site cavity but quick diversification of product specificity occurs. The threshold concentration of Malonyl-CoA and P-coumaroyl-CoA were predicted, maximisation of this concentration leads to enhanced flavonoid biosynthesis. Inhibition of few enzymes may also maximise the flavonoid biosynthesis if appropriate inhibitors are used and a constant supply of Malonyl-CoA and P-Coumaroyl-CoA is maintained using activator molecules. Chalcone synthase Mutants diversify product specificity that occurs without loss of catalytic activity and any conformational changes.

Myocardial energy metabolism in ischemic preconditioning and cardioplegia: A metabolic control analysis

2005 ◽  
Vol 278 (1-2) ◽  
pp. 223-232 ◽  
Author(s):  
Achim M. Vogt ◽  
Albrecht Elsässer ◽  
Anja Pott-Beckert ◽  
Cordula Ackermann ◽  
Sven Y. Vetter ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Metabolic Control ◽  
Ischemic Preconditioning ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Myocardial Energy Metabolism

scholarly journals Quasi-linear relationship between Gibbs free energy of ATP hydrolysis and power output in human forearm muscle

1995 ◽  
Vol 268 (6) ◽  
pp. C1474-C1484 ◽  
Author(s):  
J. A. Jeneson ◽  
H. V. Westerhoff ◽  
T. R. Brown ◽  
C. J. Van Echteld ◽  
R. Berger
Keyword(s):  
Skeletal Muscle ◽  
Free Energy ◽  
Oxidative Phosphorylation ◽  
Power Output ◽  
Atp Hydrolysis ◽  
Adenine Nucleotide ◽  
Resonance Spectroscopy ◽  
Mammalian Skeletal Muscle ◽  
Flexor Muscle ◽  
Linear Description

The postulated strictly linear descriptions of the rate dependence of oxidative phosphorylation in skeletal muscle on the free energy of ATP hydrolysis (delta GP) over the range of physiological steady states fail to harmonize with reported findings of identical basal respiration rates in mammalian muscles at different delta GP values. The relevance of an extension of the strictly linear description to a description deriving from enzyme kinetics that predicts a sigmoidal dependence was investigated in human finger flexor muscle using 31P-nuclear magnetic resonance spectroscopy. At constant pH 7.0, the experimental variation of adenine nucleotide concentrations with power output, which reflects the rate of oxidative phosphorylation, was compared with predictions by various formulations of adenine nucleotide control of respiration. The quasi-linear sigmoidal description was found to be statistically equivalent but physiologically superior to the strictly linear description. The predicted maximal oxidatively sustained steady-state power output and rate-dependent sensitivity of respiration to changes in delta GP were in agreement both with theoretical considerations and with experimental observations in the present study and other studies of intact mammalian skeletal muscle.

scholarly journals In vivo modular control analysis of energy metabolism in contracting skeletal muscle

2008 ◽  
Vol 414 (3) ◽  
pp. 391-397 ◽  
Author(s):  
Laurent M. Arsac ◽  
Christophe Beuste ◽  
Sylvain Miraux ◽  
Véronique Deschodt-Arsac ◽  
Eric Thiaudiere ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Contractile Activity ◽  
Metabolic Control Analysis ◽  
Resonance Spectroscopy ◽  
Control Analysis ◽  
Modular Control ◽  
Anaesthetized Rats ◽  
Control Pattern

We used 31P MRS (magnetic resonance spectroscopy) measurements of energetic intermediates [ATP, Pi and PCr (phosphocreatine)] in combination with the analytical tools of metabolic control analysis to study in vivo energy metabolism in the contracting skeletal muscle of anaesthetized rats over a broad range of workload. According to our recent MoCA (modular control analysis) used to describe regulatory mechanisms in beating heart, we defined the energetic system of muscle contraction as two modules (PCr-Producer and PCr-Consumer) connected by the energetic intermediates. Hypoxia and electrical stimulation were used in this in vivo study as reasonably selective modulations of Producer and Consumer respectively. As quantified by elasticity coefficients, the sensitivities of each module to PCr determine the control of steady-state contractile activity and metabolite concentrations. The magnitude of the elasticity of the producer was high (4.3±0.6) at low workloads and decreased 5-fold (to 0.9±0.2) at high workloads. By contrast, the elasticity of the consumer remained low (0.5–1.2) over the range of metabolic rates studied. The control exerted by each module over contraction was calculated from these elasticities. The control of contraction was found on the consumer at low workloads and then swung to the producer, due to the workload-dependent decrease in the elasticity of producer. The workload-dependent elasticity and control pattern of energy production in muscle is a major difference from heart. Since module rate and elasticity depend on the concentrations of substrates and products, the absence of homoeostasis of the energetic intermediates in muscle, by contrast with heart, is probably the origin of the workload-dependent elasticity of the producer module.

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