Oxidative ATP synthesis in skeletal muscle is controlled by substrate feedback

2007 ◽  
Vol 292 (1) ◽  
pp. C115-C124 ◽  
Author(s):  
Fan Wu ◽  
Jeroen A. L. Jeneson ◽  
Daniel A. Beard
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Atp Hydrolysis ◽  
Adenine Nucleotide ◽  
Atp Synthesis ◽  
Biophysical Model ◽  
Resonance Spectroscopy ◽  
Flexor Muscle ◽  
Matched Data ◽  
The Impact

Data from 31P-nuclear magnetic resonance spectroscopy of human forearm flexor muscle were analyzed based on a previously developed model of mitochondrial oxidative phosphorylation ( PLoS Comp Bio 1: e36, 2005) to test the hypothesis that substrate level (concentrations of ADP and inorganic phosphate) represents the primary signal governing the rate of mitochondrial ATP synthesis and maintaining the cellular ATP hydrolysis potential in skeletal muscle. Model-based predictions of cytoplasmic concentrations of phosphate metabolites (ATP, ADP, and Pi) matched data obtained from 20 healthy volunteers and indicated that as work rate is varied from rest to submaximal exercise commensurate increases in the rate of mitochondrial ATP synthesis are effected by changes in concentrations of available ADP and Pi. Additional data from patients with a defect of complex I of the respiratory chain and a patient with a deficiency in the mitochondrial adenine nucleotide translocase were also predicted the by the model by making the appropriate adjustments to the activities of the affected proteins associates with the defects, providing both further validation of the biophysical model of the control of oxidative phosphorylation and insight into the impact of these diseases on the ability of the cell to maintain its energetic state.

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.

Recovery of free ADP, Pi, and free energy of ATP hydrolysis in human skeletal muscle

1998 ◽  
Vol 85 (6) ◽  
pp. 2140-2145 ◽  
Author(s):  
Henning Wackerhage ◽  
Uwe Hoffmann ◽  
Dieter Essfeld ◽  
Dieter Leyk ◽  
Klaus Mueller ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Nuclear Magnetic Resonance ◽  
Free Energy ◽  
Magnetic Resonance ◽  
Oxidative Phosphorylation ◽  
Human Skeletal Muscle ◽  
Atp Hydrolysis ◽  
Resonance Spectroscopy ◽  
Atp Production ◽  
Production And Consumption

We measured significant undershoots of the concentrations of free ADP ([ADP]) and Pi([Pi]) and the free energy of ATP hydrolysis (Δ G ATP) below initial resting levels during recovery from severe ischemic exercise with 31P-nuclear magnetic resonance spectroscopy in 11 healthy sports students. Undershoots of the rate of oxidative phosphorylation would be predicted if the rate of oxidative phosphorylation would depend solely on free [ADP], [Pi], or Δ G ATP. However, undershoots of the rate of oxidative phosphorylation have not been reported in the literature. Furthermore, undershoots of the rate of oxidative phosphorylation are unlikely because there is evidence that a balance between ATP production and consumption cannot be achieved if an undershoot of the rate of oxidative phosphorylation actually occurs. Therefore, oxidative phosphorylation seems to depend not only on free [ADP], [Pi], or Δ G ATP. An explanation is that acidosis-related or other factors control oxidative phosphorylation additionally, at least under some conditions.

scholarly journals Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans

2015 ◽  
Vol 309 (4) ◽  
pp. R378-R388 ◽  
Author(s):  
Gwenael Layec ◽  
Joel D. Trinity ◽  
Corey R. Hart ◽  
Seong-Eun Kim ◽  
H. Jonathan Groot ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plantar Flexion ◽  
Atp Synthesis ◽  
The Elderly ◽  
Exercise Intolerance ◽  
Resonance Spectroscopy ◽  
Metabolic Demand ◽  
Age Related ◽  
Exercise Induced ◽  
The Impact

Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used 31P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min−1·W−1, respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age.

scholarly journals Accuracy and precision of quantitative 31P-MRS measurements of human skeletal muscle mitochondrial function

2016 ◽  
Vol 311 (2) ◽  
pp. E358-E366 ◽  
Author(s):  
Gwenael Layec ◽  
Jayson R. Gifford ◽  
Joel D. Trinity ◽  
Corey R. Hart ◽  
Ryan S. Garten ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vastus Lateralis ◽  
Muscle Fibers ◽  
Atp Synthesis ◽  
Synthesis Rate ◽  
Resonance Spectroscopy ◽  
Phosphorylation Potential ◽  
Accuracy And Precision ◽  
Mitochondrial Capacity

Although theoretically sound, the accuracy and precision of 31P-magnetic resonance spectroscopy (31P-MRS) approaches to quantitatively estimate mitochondrial capacity are not well documented. Therefore, employing four differing models of respiratory control [linear, kinetic, and multipoint adenosine diphosphate (ADP) and phosphorylation potential], this study sought to determine the accuracy and precision of 31P-MRS assessments of peak mitochondrial adenosine-triphosphate (ATP) synthesis rate utilizing directly measured peak respiration (State 3) in permeabilized skeletal muscle fibers. In 23 subjects of different fitness levels, 31P-MRS during a 24-s maximal isometric knee extension and high-resolution respirometry in muscle fibers from the vastus lateralis was performed. Although significantly correlated with State 3 respiration ( r = 0.72), both the linear (45 ± 13 mM/min) and phosphorylation potential (47 ± 16 mM/min) models grossly overestimated the calculated in vitro peak ATP synthesis rate ( P < 0.05). Of the ADP models, the kinetic model was well correlated with State 3 respiration ( r = 0.72, P < 0.05), but moderately overestimated ATP synthesis rate ( P < 0.05), while the multipoint model, although being somewhat less well correlated with State 3 respiration ( r = 0.55, P < 0.05), most accurately reflected peak ATP synthesis rate. Of note, the PCr recovery time constant (τ), a qualitative index of mitochondrial capacity, exhibited the strongest correlation with State 3 respiration ( r = 0.80, P < 0.05). Therefore, this study reveals that each of the 31P-MRS data analyses, including PCr τ, exhibit precision in terms of mitochondrial capacity. As only the multipoint ADP model did not overstimate the peak skeletal muscle mitochondrial ATP synthesis, the multipoint ADP model is the only quantitative approach to exhibit both accuracy and precision.

Use of intramuscular triacylglycerol as a substrate source during exercise in humans

2004 ◽  
Vol 97 (4) ◽  
pp. 1170-1187 ◽  
Author(s):  
Luc J. C. van Loon
Keyword(s):  
Skeletal Muscle ◽  
Effective Means ◽  
Indirect Evidence ◽  
Atp Synthesis ◽  
Exercise Duration ◽  
Resonance Spectroscopy ◽  
Skeletal Muscle Insulin Resistance ◽  
Exercise In Humans ◽  
Substrate Source

Fat and carbohydrate are the principal substrates that fuel aerobic ATP synthesis in skeletal muscle. Most endogenous fat is stored as triacylglycerol in subcutaneous and deep visceral adipose tissue. Smaller quantities of triacylglycerol are deposited as lipid droplets inside skeletal muscle fibers. The potential role of intramyocellular triacylglycerol (IMTG) as a substrate source during exercise in humans has recently regained much of its interest because of the proposed functional relationship between IMTG accumulation and the development of skeletal muscle insulin resistance. Exercise likely represents an effective means to prevent excess IMTG accretion by stimulating its rate of oxidation. However, there is much controversy on the actual contribution of the IMTG pool as a substrate source during exercise. The apparent discrepancy in the literature likely stems from methodological difficulties that have been associated with the methods used to estimate IMTG oxidation during exercise. However, recent studies using stable isotope methodology,1H-magnetic resonance spectroscopy, and electron and/or immunofluorescence microscopy all support the contention that the IMTG pool can function as an important substrate source during exercise. Although more research is warranted, IMTG mobilization and/or oxidation during exercise seem to be largely determined by exercise intensity, exercise duration, macronutrient composition of the diet, training status, gender, and/or age. In addition, indirect evidence suggests that the capacity to mobilize and/or oxidize IMTG is substantially impaired in an obese and/or Type 2 diabetic state. As we now become aware that skeletal muscle has an enormous capacity to oxidize IMTG stores during exercise, more research is warranted to develop combined exercise, nutritional, and/or pharmacological interventions to effectively stimulate IMTG oxidation in sedentary, obese, and/or Type 2 diabetes patients.

Increased Oxidative and Delayed Glycogenolytic ATP Synthesis in Exercising Skeletal Muscle of Obese (Insulin-Resistant) Zucker Rats

1996 ◽  
Vol 91 (6) ◽  
pp. 691-702 ◽  
Author(s):  
A. L. Sanderson ◽  
G. J. Kemp ◽  
C. H. Thompson ◽  
G. K. Radda
Keyword(s):  
Skeletal Muscle ◽  
Water Content ◽  
Atp Synthesis ◽  
Intracellular Water ◽  
Zucker Rats ◽  
Resonance Spectroscopy ◽  
Metabolic Efficiency ◽  
Marker Enzyme ◽  
Insulin Resistant ◽  
Kinetics Of

1. To examine metabolic correlates of insulin resistance in skeletal muscle, we used 31P magnetic resonance spectroscopy to study glycogenolytic and oxidative ATP synthesis in leg muscle of lean and obese Zucker rats in vivo during 6 min sciatic nerve stimulation at 2 Hz. 2. The water content of resting muscle was reduced by 21 ± 7% in obese (insulin-resistant) animals compared with lean animals, whereas the lipid content was increased by 140 ± 70%. These results suggest that intracellular water content was reduced by 17% in obese animals. 3. During exercise, although twitch tensions were not significantly different in the two groups, rates of total ATP synthesis (expressed per litre of intracellular water) were 48 ± 20% higher in obese animals, suggesting a 50 ± 8% reduction in intrinsic ‘metabolic efficiency’. Changes in phosphocreatine and ADP concentration were significantly greater in obese animals than in lean animals, whereas changes in intracellular pH did not differ. 4. These results imply that oxidative ATP synthesis during exercise is activated earlier in obese animals than in lean animals. This difference was not fully accounted for by the greater increase in the concentration of the mitochondrial activating signal ADP. Neither the post-exercise recovery kinetics of phosphocreatine nor the muscle content of the mitochondrial marker enzyme citrate synthase was significantly different in the two groups. The increased oxidative ATP synthesis in exercise must therefore be due to altered kinetics of mitochondrial activation by signals other than ADP. 5. Thus, the insulin-resistant muscle of obese animals may compensate for its decreased efficiency (and consequent increased need for ATP) by increased reliance on oxidative ATP synthesis.

Limits to sustainable muscle performance: interaction between glycolysis and oxidative phosphorylation

2001 ◽  
Vol 204 (18) ◽  
pp. 3189-3194 ◽  
Author(s):  
Kevin E. Conley ◽  
William F. Kemper ◽  
Gregory J. Crowther
Keyword(s):  
Oxidative Phosphorylation ◽  
Atp Synthesis ◽  
Oxidative Capacity ◽  
Human Muscle ◽  
Muscle Performance ◽  
Glycolytic Flux ◽  
Resonance Spectroscopy ◽  
Sustainable Performance ◽  
Atp Supply

SUMMARY This paper proposes a mechanism responsible for setting the sustainable level of muscle performance. Our contentions are that the sustainable work rate is determined (i) at the muscle level, (ii) by the ability to maintain ATP supply and (iii) by the products of glycolysis that may inhibit the signal for oxidative phosphorylation. We argue below that no single factor ‘limits’ sustainable performance, but rather that the flux through and the interaction between glycolysis and oxidative phosphorylation set the level of sustainable ATP supply. This argument is based on magnetic resonance spectroscopy measurements of the sources and sinks for energy in vivo in human muscle and rattlesnake tailshaker muscle during sustained contractions. These measurements show that glycolysis provides between 20% (human muscle) and 40% (tailshaker muscle) of the ATP supply during sustained contractions in these muscles. We cite evidence showing that this high glycolytic flux does not reflect an O2 limitation or mitochondria operating at their capacity. Instead, this flux reflects a pathway independent of oxidative phosphorylation for ATP supply during aerobic exercise. The consequence of this high glycolytic flux is accumulation of H+, which we argue inhibits the rise in the signal activating oxidative phosphorylation, thereby restricting oxidative ATP supply to below the oxidative capacity. Thus, both glycolysis and oxidative phosphorylation play important roles in setting the highest steady-state ATP synthesis flux and thereby determine the sustainable level of work by exercising muscle.

scholarly journals Alteration of mitochondrial oxidative phosphorylation in aged skeletal muscle involves modification of adenine nucleotide translocator

2010 ◽  
Vol 1797 (2) ◽  
pp. 143-151 ◽  
Author(s):  
Gilles Gouspillou ◽  
Isabelle Bourdel-Marchasson ◽  
Richard Rouland ◽  
Guillaume Calmettes ◽  
Jean-Michel Franconi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Adenine Nucleotide ◽  
Adenine Nucleotide Translocator ◽  
Mitochondrial Oxidative Phosphorylation

Effects of acute exercise on lipid content and dietary lipid uptake in liver and skeletal muscle of lean and diabetic rats

2015 ◽  
Vol 309 (10) ◽  
pp. E874-E883 ◽  
Author(s):  
Sharon Janssens ◽  
Richard A. M. Jonkers ◽  
Albert K. Groen ◽  
Klaas Nicolay ◽  
Luc J. C. van Loon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Content ◽  
Acute Exercise ◽  
Dietary Lipid ◽  
Diabetic Rats ◽  
Dietary Lipids ◽  
Treadmill Running ◽  
Resonance Spectroscopy ◽  
Lipid Uptake ◽  
The Impact

Insulin resistance is associated with ectopic lipid accumulation. Physical activity improves insulin sensitivity, but the impact of exercise on lipid handling in insulin-resistant tissues remains to be elucidated. The present study characterizes the effects of acute exercise on lipid content and dietary lipid partitioning in liver and skeletal muscle of lean and diabetic rats by use of magnetic resonance spectroscopy (MRS). After baseline measurements, rats were randomized to exercise or no-exercise groups. A subset of animals was subjected to MRS directly after 1 h of treadmill running for measurement of total intrahepatocellular lipid (IHCL) and intramyocellular lipid (IMCL) content ( n = 7 lean and diabetic rats). The other animals were administered 13C-labeled lipids orally after treadmill visit (with or without exercise) followed by MRS measurements after 4 and 24 h to determine the 13C enrichment of IHCL and IMCL ( n = 8 per group). Total IHCL and IMCL content were fivefold higher in diabetic vs. lean rats ( P < 0.001). Exercise did not significantly affect IHCL content but reduced IMCL by 25 ± 7 and 33 ± 4% in lean and diabetic rats ( P < 0.05), respectively. Uptake of dietary lipids in liver and muscle was 2.3-fold greater in diabetic vs. lean rats ( P < 0.05). Prior exercise did not significantly modulate dietary lipid uptake into muscle, but in liver of both lean and diabetic rats, lipid uptake was 44% reduced after acute exercise ( P < 0.05). In conclusion, IMCL but not IHCL represents a viable substrate source during exercise in both lean and diabetic rats, and exercise differentially affects dietary lipid uptake in muscle and liver.

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