scholarly journals Muscle oxygenation and ATP turnover when blood flow is impaired by vascular disease

2002 ◽  
Vol 16 (3-4) ◽  
pp. 317-334 ◽  
Author(s):  
Graham J. Kemp ◽  
Neil Roberts ◽  
William E. Bimson ◽  
Ali Bakran ◽  
Simon P. Frostick
Keyword(s):  
Vascular Disease ◽  
Near Infrared ◽  
Atp Synthesis ◽  
Normal Subjects ◽  
Synthesis Rate ◽  
Resonance Spectroscopy ◽  
Muscle Creatine Kinase ◽  
Muscle Energy Metabolism ◽  
Atp Supply

In exercising muscle, creatine kinase ensures that mismatch between ATP supply and ATP use results in net phosphocreatine (PCr) splitting. This,inter alia, makes31P magnetic resonance spectroscopy a useful tool for studying muscle ‘energy metabolism’ noninvasivelyin vivo. We combined this with near–infrared spectroscopy (NIRS) to study ATP synthesis and oxygenation in calf muscle of normal subjects and patients with peripheral vascular disease. Experimental and clinical details and basic data have been published elsewhere (G.J. Kemp et al.,Journal of Vascular Surgery34 (2001), 1103–10); we here propose an analysis of interactions between metabolic ‘error signals’ and cellular PO2(estimated from NIRS changes, provisionally assumed to reflect deoxymyoglobin). Post–exercise PCr recovery is monoexponential, and the linear relationship between PCr resynthesis rate (= oxidative ATP synthesis) and the perturbation in PCr (conceptually the simplest error signal) is consistent with negative feedback. In patients the inferred ‘mitochondrial capacity’ (= oxidative ATP synthesis at ‘zero’ PCr) is decreased by 53±6%, leading to reduced oxidative ATP contribution in exercise, because of increased deoxygenation. Increased PCr perturbation partially outweighs cellular hypoxia, but as low cellular PO2is required for capillary–mitochondrion O2diffusion, rate–signal relationships may overstate maximum oxidative ATP synthesis rate.

scholarly journals Mitochondrial function and increased convective O2 transport: implications for the assessment of mitochondrial respiration in vivo

2013 ◽  
Vol 115 (6) ◽  
pp. 803-811 ◽  
Author(s):  
Gwenael Layec ◽  
Luke J. Haseler ◽  
Joel D. Trinity ◽  
Corey R. Hart ◽  
Xin Liu ◽  
...  
Keyword(s):  
Blood Flow ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Near Infrared ◽  
Reactive Hyperemia ◽  
Atp Synthesis ◽  
Synthesis Rate ◽  
Resonance Spectroscopy ◽  
Doppler Ultrasound Imaging

Although phosphorus magnetic resonance spectroscopy (31P-MRS)-based evidence suggests that in vivo peak mitochondrial respiration rate in young untrained adults is limited by the intrinsic mitochondrial capacity of ATP synthesis, it remains unknown whether a large, locally targeted increase in convective O2 delivery would alter this interpretation. Consequently, we examined the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last minute of exercise, on oxygen delivery and mitochondrial function in the calf muscle of nine young adults compared with free-flow conditions (FF). To this aim, we used an integrative experimental approach combining 31P-MRS, Doppler ultrasound imaging, and near-infrared spectroscopy. Limb blood flow [area under the curve (AUC), 1.4 ± 0.8 liters in FF and 2.5 ± 0.3 liters in RH, P < 0.01] and convective O2 delivery (AUC, 0.30 ± 0.16 liters in FF and 0.54 ± 0.05 liters in RH, P < 0.01), were significantly increased in RH compared with FF. RH was also associated with significantly higher capillary blood flow ( P < 0.05) and faster tissue reoxygenation mean response times (70 ± 15 s in FF and 24 ± 15 s in RH, P < 0.05). This resulted in a 43% increase in estimated peak mitochondrial ATP synthesis rate (29 ± 13 mM/min in FF and 41 ± 14 mM/min in RH, P < 0.05) whereas the phosphocreatine (PCr) recovery time constant in RH was not significantly different ( P = 0.22). This comprehensive assessment of local skeletal muscle O2 availability and utilization in untrained subjects reveals that mitochondrial function, assessed in vivo by 31P-MRS, is limited by convective O2 delivery rather than an intrinsic mitochondrial limitation.

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 Effects of altered pyruvate dehydrogenase activity on contracting skeletal muscle bioenergetics

2019 ◽  
Vol 316 (1) ◽  
pp. R76-R86 ◽  
Author(s):  
Jonathan D. Kasper ◽  
Ronald A. Meyer ◽  
Daniel A. Beard ◽  
Robert W. Wiseman
Keyword(s):  
Steady State ◽  
Pyruvate Dehydrogenase ◽  
Primary Source ◽  
Atp Synthesis ◽  
Synthesis Rate ◽  
Resonance Spectroscopy ◽  
Phosphate Potential ◽  
Muscle Energetics ◽  
Atp Production

During aerobic exercise (>65% of maximum oxygen consumption), the primary source of acetyl-CoA to fuel oxidative ATP synthesis in muscle is the pyruvate dehydrogenase (PDH) reaction. This study investigated how regulation of PDH activity affects muscle energetics by determining whether activation of PDH with dichloroacetate (DCA) alters the dynamics of the phosphate potential of rat gastrocnemius muscle during contraction. Twitch contractions were induced in vivo over a broad range of intensities to sample submaximal and maximal aerobic workloads. Muscle phosphorus metabolites were measured in vivo before and after DCA treatment by phosphorus nuclear magnetic resonance spectroscopy. At rest, DCA increased PDH activation compared with control (90 ± 12% vs. 23 ± 3%, P < 0.05), with parallel decreases in inorganic phosphate (Pi) of 17% (1.4 ± 0.2 vs. 1.7 ± 0.1 mM, P < 0.05) and an increase in the free energy of ATP hydrolysis (ΔGATP) (−66.2 ± 0.3 vs. −65.6 ± 0.2 kJ/mol, P < 0.05). During stimulation DCA increased steady-state phosphocreatine (PCr) and the magnitude of ΔGATP, with concomitant reduction in Pi and ADP concentrations. These effects were not due to kinetic alterations in PCr hydrolysis, resynthesis, or glycolytic ATP production and altered the flow-force relationship between mitochondrial ATP synthesis rate and ΔGATP. DCA had no significant effect at 1.0- to 2.0-Hz stimulation because physiological mechanisms at these high stimulation levels cause maximal activation of PDH. These data support a role of PDH activation in the regulation of the energetic steady state by altering the phosphate potential (ΔGATP) at rest and during contraction.

scholarly journals Aerobic Growth of Escherichia coli Is Reduced, and ATP Synthesis Is Selectively Inhibited when Five C-terminal Residues Are Deleted from the ϵ Subunit of ATP Synthase

2015 ◽  
Vol 290 (34) ◽  
pp. 21032-21041 ◽  
Author(s):  
Naman B. Shah ◽  
Thomas M. Duncan
Keyword(s):  
Escherichia Coli ◽  
Atp Synthase ◽  
Atp Hydrolysis ◽  
Atp Synthesis ◽  
Intrinsic Rate ◽  
Synthesis Rate ◽  
Final Segment ◽  
Rotary Catalysis

F-type ATP synthases are rotary nanomotor enzymes involved in cellular energy metabolism in eukaryotes and eubacteria. The ATP synthase from Gram-positive and -negative model bacteria can be autoinhibited by the C-terminal domain of its ϵ subunit (ϵCTD), but the importance of ϵ inhibition in vivo is unclear. Functional rotation is thought to be blocked by insertion of the latter half of the ϵCTD into the central cavity of the catalytic complex (F1). In the inhibited state of the Escherichia coli enzyme, the final segment of ϵCTD is deeply buried but has few specific interactions with other subunits. This region of the ϵCTD is variable or absent in other bacteria that exhibit strong ϵ-inhibition in vitro. Here, genetically deleting the last five residues of the ϵCTD (ϵΔ5) caused a greater defect in respiratory growth than did the complete absence of the ϵCTD. Isolated membranes with ϵΔ5 generated proton-motive force by respiration as effectively as with wild-type ϵ but showed a nearly 3-fold decrease in ATP synthesis rate. In contrast, the ϵΔ5 truncation did not change the intrinsic rate of ATP hydrolysis with membranes. Further, the ϵΔ5 subunit retained high affinity for isolated F1 but reduced the maximal inhibition of F1-ATPase by ϵ from >90% to ∼20%. The results suggest that the ϵCTD has distinct regulatory interactions with F1 when rotary catalysis operates in opposite directions for the hydrolysis or synthesis of ATP.

Simultaneous in vivo measurements of HbO2 saturation and PCr kinetics after exercise in normal humans

1994 ◽  
Vol 77 (1) ◽  
pp. 5-10 ◽  
Author(s):  
K. K. McCully ◽  
S. Iotti ◽  
K. Kendrick ◽  
Z. Wang ◽  
J. D. Posner ◽  
...  
Keyword(s):  
Infrared Spectroscopy ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Time Constant ◽  
Near Infrared Spectroscopy ◽  
Near Infrared ◽  
Plantar Flexion ◽  
Resonance Spectroscopy ◽  
Ph Values

Simultaneous measurements of phosphocreatine (PCr) and oxyhemoglobin (HbO2) saturation were made during recovery from exercise in calf muscles of five male subjects. PCr was measured using magnetic resonance spectroscopy in a 2.0-T 78-cm-bore magnet with a 9-cm-diam surface coil. Relative HbO2 saturation was measured as the difference in absorption of 750- and 850-nm light with use of near-infrared spectroscopy. The light source and detectors were 3 cm apart. Exercise consisted of isokinetic plantar flexion in a supine position. Two 5-min submaximal protocols were performed with PCr depletion to 60% of resting values and with pH values of > 7.0. Then two 1-min protocols of rapid plantar flexion were performed to deplete PCr values to 5–20% of resting values with pH values of < 6.8. Areas of PCr peaks (every 8 s) and HbO2 saturation (every 1 s) were fit to a monoexponential function, and a time constant was calculated. The PCr time constant was larger after maximal exercise (68.3 +/- 10.5 s) than after submaximal exercise (36.0 +/- 6.5 s), which is consistent with the effects of low pH on PCr recovery. HbO2 resaturation approximated submaximal PCr recovery and was not different between maximal (29.4 +/- 5.5 s) and submaximal (27.6 +/- 6.0 s) exercise. We conclude that magnetic resonance spectroscopy measurements of PCr recovery and near-infrared spectroscopy measurements of recovery of HbO2 saturation provide similar information as long as muscle pH remains near 7.0.

scholarly journals Nuclear Expression of a Mitochondrial DNA Gene: Mitochondrial Targeting of Allotopically Expressed Mutant ATP6 in Transgenic Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
David A. Dunn ◽  
Carl A. Pinkert
Keyword(s):  
Mitochondrial Dna ◽  
Atp Synthesis ◽  
Serum Lactate ◽  
Superior Performance ◽  
Synthesis Rate ◽  
Mitochondrial Targeting ◽  
Biochemical Tests ◽  
Balance Beam ◽  
Protein Levels

Nuclear encoding of mitochondrial DNA transgenes followed by mitochondrial targeting of the expressed proteins (allotopic expression; AE) represents a potentially powerful strategy for creating animal models of mtDNA disease. Mice were created that allotopically express either a mutant (A6M) or wildtype (A6W)mt-Atp6transgene. Compared to non-transgenic controls, A6M mice displayed neuromuscular and motor deficiencies (wire hang, pole, and balance beam analyses;P<0.05), no locomotor differences (gait analysis;P<0.05) and enhanced endurance in Rota-Rod evaluations (P<0.05). A6W mice exhibited inferior muscle strength (wire hang test;P<0.05), no difference in balance beam footsteps, accelerating Rota-Rod, pole test and gait analyses; (P<0.05) and superior performance in balance beam time-to-cross and constant velocity Rota-Rod analyses (P<0.05) in comparison to non-transgenic control mice. Mice of both transgenic lines did not differ from non-transgenic controls in a number of bioenergetic and biochemical tests including measurements of serum lactate and mitochondrial MnSOD protein levels, ATP synthesis rate, and oxygen consumption (P>0.05). This study illustrates a mouse model capable of circumventingin vivomitochondrial mutations. Moreover, it provides evidence supporting AE as a tool for mtDNA disease research with implications in development of DNA-based therapeutics.

scholarly journals Complex I is bypassed during high intensity exercise

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Avlant Nilsson ◽  
Elias Björnson ◽  
Mikael Flockhart ◽  
Filip J. Larsen ◽  
Jens Nielsen
Keyword(s):  
High Intensity ◽  
Complex I ◽  
Atp Synthesis ◽  
Metabolic Model ◽  
High Intensity Exercise ◽  
Whole Body ◽  
Synthesis Rate ◽  
Proteomics Data ◽  
Exercise Tests

Abstract Human muscles are tailored towards ATP synthesis. When exercising at high work rates muscles convert glucose to lactate, which is less nutrient efficient than respiration. There is hence a trade-off between endurance and power. Metabolic models have been developed to study how limited catalytic capacity of enzymes affects ATP synthesis. Here we integrate an enzyme-constrained metabolic model with proteomics data from muscle fibers. We find that ATP synthesis is constrained by several enzymes. A metabolic bypass of mitochondrial complex I is found to increase the ATP synthesis rate per gram of protein compared to full respiration. To test if this metabolic mode occurs in vivo, we conduct a high resolved incremental exercise tests for five subjects. Their gas exchange at different work rates is accurately reproduced by a whole-body metabolic model incorporating complex I bypass. The study therefore shows how proteome allocation influences metabolism during high intensity exercise.

scholarly journals Local In Vivo Measures of Muscle Lipid and Oxygen Consumption Change in Response to Combined Vitamin D Repletion and Aerobic Training in Older Adults

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 930 ◽  
Author(s):  
D. Travis Thomas ◽  
David M. Schnell ◽  
Maja Redzic ◽  
Mingjun Zhao ◽  
Hideat Abraha ◽  
...  
Keyword(s):  
Older Adults ◽  
Vitamin D ◽  
Near Infrared ◽  
Aerobic Training ◽  
Combined Treatment ◽  
Tissue Level ◽  
Correlation Spectroscopy ◽  
Resonance Spectroscopy ◽  
Metabolic Dysfunction

Intramyocellular (IMCL), extramyocellular lipid (EMCL), and vitamin D deficiency are associated with muscle metabolic dysfunction. This study compared the change in [IMCL]:[EMCL] following the combined treatment of vitamin D and aerobic training (DAT) compared with vitamin D (D), aerobic training (AT), and control (CTL). Male and female subjects aged 60–80 years with a BMI ranging from 18.5–34.9 and vitamin D status of ≤32 ng/mL (25(OH)D) were recruited to randomized, prospective clinical trial double-blinded for supplement with a 2 × 2 factorial design. Cholecalciferol (Vitamin D3) (10,000 IU × 5 days/week) or placebo was provided for 13 weeks and treadmill aerobic training during week 13. Gastrocnemius IMCL and EMCL were measured with magnetic resonance spectroscopy (MRS) and MRI. Hybrid near-infrared diffuse correlation spectroscopy measured hemodynamics. Group differences in IMCL were observed when controlling for baseline IMCL (p = 0.049). DAT was the only group to reduce IMCL from baseline, while a mean increase was observed in all other groups combined (p = 0.008). IMCL reduction and the corresponding increase in rVO2 at study end (p = 0.011) were unique to DAT. Vitamin D, when combined with exercise, may potentiate the metabolic benefits of exercise by reducing IMCL and increasing tissue-level VO2 in healthy, older adults.

scholarly journals Noninvasive Measurements of Human Brain Temperature Using Volume-Localized Proton Magnetic Resonance Spectroscopy

1997 ◽  
Vol 17 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Ron Corbett ◽  
Abbot Laptook ◽  
Paul Weatherall
Keyword(s):  
Magnetic Resonance ◽  
Frontal Lobe ◽  
Mr Spectroscopy ◽  
Brain Temperature ◽  
Human Subjects ◽  
Normal Subjects ◽  
Whole Body ◽  
Resonance Spectroscopy ◽  
Noninvasive Measurements

Elucidation of the role of cerebral hyperthermia as a secondary factor that worsens outcome after brain injury, and the therapeutic application of modest brain hypothermia would benefit from noninvasive measurements of absolute brain temperature. The present study was performed to evaluate the feasibility of using 1H magnetic resonance (MR) spectroscopy to measure absolute brain temperature in human subjects on a clinical imaging spectroscopy system operating at a field strength of 1.5 T. In vivo calibration results were obtained from swine brain during whole-body heating and cooling, with concurrent measurements of brain temperature via implanted probes. Plots of the frequency differences between the in vivo MR peaks of water and N-acetyl-aspartate and related compounds (NAX), or water and choline and other trimethylamines versus brain temperature were linear over the temperature range studied (28–40°C). These relationships were used to estimate brain temperature from 1H MR spectra obtained from 10 adult human volunteers from 4 cm3-volumes selected from the frontal lobe and thalamus. Oral and forehead temperatures were monitored concurrently with MR data collection to verify normothermia in all the subjects studied. Temperatures determined using N-acetyl-aspartate or choline as the chemical shift reference did not differ significantly, and therefore results from these estimates were averaged. The brain temperature (mean ± SD) measured from the frontal lobe (37.2 = 0.6°C) and thalamus (37.7 ± 0.6°C) were significantly different from each other (paired t-test, p = 0.035). We conclude that 1H MR spectroscopy provides a viable noninvasive means of measuring regional brain temperatures in normal subjects and is a promising approach for measuring temperatures in brain-injured subjects.

Calf Muscle Metabolism in Venous Insufficiency

1993 ◽  
Vol 8 (2) ◽  
pp. 58-61
Author(s):  
L. J. Hands ◽  
G. J. Kemp ◽  
A. Zukowski ◽  
A. N. Nicolaides ◽  
G. K. Radda
Keyword(s):  
Venous Insufficiency ◽  
Muscle Metabolism ◽  
Calf Muscle ◽  
Resonance Spectroscopy ◽  
Metabolic Recovery ◽  
Glycolytic Activity ◽  
Muscle Energy ◽  
Muscle Energy Metabolism ◽  
Phosphorus Metabolites

Objectives: To study the effect of deep venous insufficiency on calf muscle energy metabolism. Design: A paired study of affected and unaffected calf muscle in seven patients with unilateral lower limb deep venous insufficiency. Investigations: Phosphorus-31 magnetic resonance spectroscopy was used to study changes in vivo in pH, phosphocreatine and other phosphorus metabolites during and after exercise. Results: Glycolytic activity was increased in the affected muscle at the start of exercise but metabolic recovery following exercise was normal. Conclusions: Oxidative phosphorylation is impaired, at least at the start of exercise, but appears normal immediately after exercise. This may be due to inadequate blood flow, perhaps secondary to the rise in intramuscular pressure that occurs with exercise.

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