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1.
Molecular correlates of MRS-based 31 phosphocreatine muscle resynthesis rate in healthy adults.
Darpolor, MM, Singh, M, Covington, J, Hanet, S, Ravussin, E, Carmichael, OT
NMR in biomedicine. 2021;(1):e4402
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Abstract
Dynamic phosphorus MRS (31 P-MRS) is a method used for in vivo studies of skeletal muscle energetics including measurements of phosphocreatine (PCr) resynthesis rate during recovery of submaximal exercise. However, the molecular events associated with the PCr resynthesis rate are still under debate. We assessed vastus lateralis PCr resynthesis rate from 31 P-MRS spectra collected from healthy adults as part of the CALERIE II study (caloric restriction), and assessed associations between PCr resynthesis and muscle mitochondrial signature transcripts and proteins (NAMPT, NQO1, PGC-1α, and SIRT1). Regression analysis indicated that higher concentration of nicotinamide phosphoribosyltransferase (NAMPT) protein, a mitochondrial capacity marker, was associated with faster PCr resynthesis. However, PCr resynthesis was not associated with greater physical fitness (VO2 peak) or messenger ribonucleic acid levels of mitochondrial function markers such as NQO1, PGC-1α, and SIRT1, suggesting that the impact of these molecular signatures on PCr resynthesis may be minimal in the context of an acute exercise bout. Together, these findings suggest that 31 P-MRS based PCr resynthesis may represent a valid non-invasive surrogate marker of mitochondrial NAMPT in human skeletal muscle.
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2.
Monitoring creatine and phosphocreatine by (13)C MR spectroscopic imaging during and after (13)C4 creatine loading: a feasibility study.
Janssen, BH, Lassche, S, Hopman, MT, Wevers, RA, van Engelen, BG, Heerschap, A
Amino acids. 2016;(8):1857-66
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Abstract
Creatine (Cr) supplementation to enhance muscle performance shows variable responses among individuals and different muscles. Direct monitoring of the supplied Cr in muscles would address these differences. In this feasibility study, we introduce in vivo 3D (13)C MR spectroscopic imaging (MRSI) of the leg with oral ingestion of (13)C4-creatine to observe simultaneously Cr and phosphocreatine (PCr) for assessing Cr uptake, turnover, and the ratio PCr over total Cr (TCr) in individual muscles. (13)C MRSI was performed of five muscles in the posterior thigh in seven subjects (two males and two females of ~20 years, one 82-year-old male, and two neuromuscular patients) with a (1)H/(13)C coil in a 3T MR system before, during and after intake of 15 % (13)C4-enriched Cr. Subjects ingested 20 g Cr/day for 4 days in four 5 g doses at equal time intervals. The PCr/TCr did not vary significantly during supplementation and was similar for all subjects and investigated muscles (average 0.71 ± 0.07), except for the adductor magnus (0.64 ± 0.03). The average Cr turnover rate, assessed in male muscles, was 2.1 ± 0.7 %/day. The linear uptake rates of Cr were variable between muscles, although not significantly different. This assessment was possible in all investigated muscles of young male volunteers, but less so in muscles of the other subjects due to lower signal-to-noise ratio. Improvements for future studies are discussed. In vivo (13)C MRSI after (13)C-Cr ingestion is demonstrated for longitudinal studies of Cr uptake, turnover, and PCr/TCr ratios of individual muscles in one exam.
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Effects of exercise-induced intracellular acidosis on the phosphocreatine recovery kinetics: a 31P MRS study in three muscle groups in humans.
Layec, G, Malucelli, E, Le Fur, Y, Manners, D, Yashiro, K, Testa, C, Cozzone, PJ, Iotti, S, Bendahan, D
NMR in biomedicine. 2013;(11):1403-11
Abstract
Little is known about the metabolic differences that exist among different muscle groups within the same subjects. Therefore, we used (31)P-magnetic resonance spectroscopy ((31)P-MRS) to investigate muscle oxidative capacity and the potential effects of pH on PCr recovery kinetics between muscles of different phenotypes (quadriceps (Q), finger (FF) and plantar flexors (PF)) in the same cohort of 16 untrained adults. The estimated muscle oxidative capacity was lower in Q (29 ± 12 mM min(-1), CV(inter-subject) = 42%) as compared with PF (46 ± 20 mM min(-1), CV(inter-subject) = 44%) and tended to be higher in FF (43 ± 35 mM min(-1), CV(inter-subject) = 80%). The coefficient of variation (CV) of oxidative capacity between muscles within the group was 59 ± 24%. PCr recovery time constant was correlated with end-exercise pH in Q (p < 0.01), FF (p < 0.05) and PF (p < 0.05) as well as proton efflux rate in FF (p < 0.01), PF (p < 0.01) and Q (p = 0.12). We also observed a steeper slope of the relationship between end-exercise acidosis and PCr recovery kinetics in FF compared with either PF or Q muscles. Overall, this study supports the concept of skeletal muscle heterogeneity by revealing a comparable inter- and intra-individual variability in oxidative capacity across three skeletal muscles in untrained individuals. These findings also indicate that the sensitivity of mitochondrial respiration to the inhibition associated with cytosolic acidosis is greater in the finger flexor muscles compared with locomotor muscles, which might be related to differences in permeability in the mitochondrial membrane and, to some extent, to proton efflux rates.
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Percutaneous intervention in peripheral artery disease improves calf muscle phosphocreatine recovery kinetics: a pilot study.
West, AM, Anderson, JD, Epstein, FH, Meyer, CH, Hagspiel, KD, Berr, SS, Harthun, NL, Weltman, AL, Annex, BH, Kramer, CM
Vascular medicine (London, England). 2012;(1):3-9
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Abstract
We hypothesized that percutaneous intervention in the affected lower extremity artery would improve calf muscle perfusion and cellular metabolism in patients with claudication and peripheral artery disease (PAD) as measured by magnetic resonance imaging (MRI) and spectroscopy (MRS). Ten patients with symptomatic PAD (mean ± SD: age 57 ± 9 years; ankle-brachial index (ABI) 0.62 ± 0.17; seven males) were studied 2 months before and 10 months after lower extremity percutaneous intervention. Calf muscle phosphocreatine recovery time constant (PCr) in the revascularized leg was measured by (31)P MRS immediately after symptom-limited exercise on a 1.5-T scanner. Calf muscle perfusion was measured using first-pass gadolinium-enhanced MRI at peak exercise. A 6-minute walk and treadmill test were performed. The PCr recovery time constant improved significantly following intervention (91 ± 33 s to 52 ± 34 s, p < 0.003). Rest ABI also improved (0.62 ± 0.17 to 0.93 ± 0.25, p < 0.003). There was no difference in MRI-measured tissue perfusion or exercise parameters, although the study was underpowered for these endpoints. In conclusion, in this pilot study, successful large vessel percutaneous intervention in patients with symptomatic claudication, results in improved ABI and calf muscle phosphocreatine recovery kinetics.
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Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI.
Bejjani, A, O'Neill, J, Kim, JA, Frew, AJ, Yee, VW, Ly, R, Kitchen, C, Salamon, N, McCracken, JT, Toga, AW, et al
PloS one. 2012;(7):e38786
Abstract
Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy ((1)H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging ((1)H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.
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Influence of dietary creatine supplementation on muscle phosphocreatine kinetics during knee-extensor exercise in humans.
Jones, AM, Wilkerson, DP, Fulford, J
American journal of physiology. Regulatory, integrative and comparative physiology. 2009;(4):R1078-87
Abstract
We hypothesized that increasing skeletal muscle total creatine (Cr) content through dietary Cr supplementation would result in slower muscle phosphocreatine concentration ([PCr]) kinetics, as assessed using (31)P magnetic resonance spectroscopy, following the onset and offset of both moderate-intensity (Mod) and heavy-intensity (Hvy) exercise. Seven healthy males (age 29 +/- 6 yr, mean +/- SD) completed a series of square-wave transitions to Mod and Hvy knee extensor exercise inside the bore of a 1.5-T superconducting magnet both before and after a 5-day period of Cr loading (4x 5 g/day of creatine monohydrate). Cr supplementation resulted in an approximately 8% increase in the resting muscle [PCr]-to-[ATP] ratio (4.66 +/- 0.27 vs. 5.04 +/- 0.22; P < 0.05), consistent with a significant increase in muscle total Cr content consequent to the intervention. The time constant for muscle [PCr] kinetics was increased following Cr loading for Mod exercise (control: 15 +/- 8 vs. Cr: 25 +/- 9 s; P < 0.05) and subsequent recovery (control: 14 +/- 8 vs. Cr: 27 +/- 8 s; P < 0.05) and for Hvy exercise (control: 54 +/- 18 vs. Cr: 72 +/- 30 s; P < 0.05), but not for subsequent recovery (control: 41 +/- 11 vs. Cr: 44 +/- 6 s). The magnitude of the increase in [PCr] following Cr loading was correlated (P < 0.05) with the extent of the slowing of the [PCr] kinetics for the moderate off-transient (r = 0.92) and the heavy on-transient (r = 0.71). These data demonstrate, for the first time in humans, that an increase in muscle [PCr] results in a slowing of [PCr] dynamics in exercise and subsequent recovery.
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Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibers and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609.
Grunnet, LG, Brøns, C, Jacobsen, S, Nilsson, E, Astrup, A, Hansen, T, Pedersen, O, Poulsen, P, Quistorff, B, Vaag, A
The Journal of clinical endocrinology and metabolism. 2009;(2):596-602
Abstract
OBJECTIVE Recent studies identified the rs9939609 A-allele of the FTO (fat mass and obesity associated) gene as being associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes. METHODS Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an iv glucose tolerance test, 31phosphorous magnetic resonance spectroscopy, and 24-h whole body metabolism was measured in a respiratory chamber. RESULTS The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance, and shorter recovery half-times of phosphocreatine and inorganic phosphate after exercise in a primarily type I muscle. These relationships--except for fasting insulin--remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-h energy expenditure, or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest. CONCLUSION Increased energy efficiency--and potentially increased mitochondrial coupling--as suggested by faster recovery rates of phosphocreatine and inorganic phosphate in oxidative muscle fibers may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated with the FTO phenotype.
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Phosphocreatine kinetics in the calf muscle of patients with bilateral symptomatic peripheral arterial disease during exhaustive incremental exercise.
Esterhammer, R, Schocke, M, Gorny, O, Posch, L, Messner, H, Jaschke, W, Fraedrich, G, Greiner, A
Molecular imaging and biology. 2008;(1):30-9
Abstract
PURPOSE To investigate the relationship between the atherosclerotic lesion load determined on magnetic resonance angiography (MRA) and phosphocreatine (PCr) kinetics during incremental, exhaustive calf exercise in patients with bilateral, symptomatic peripheral arterial disease (PAD). PROCEDURES Using a 1.5 Tesla MR scanner, 26 patients with bilateral symptomatic PAD and 24 healthy male controls underwent serial phosphorus-31 MR spectroscopy (31P MRS) during incremental exercise at 2, 3, 4, and 5 Watts. For each increment and recovery, PCr time constants, amplitudes of PCr changes and pH values were calculated from the MR spectra. In patients, the run-off resistance (ROR) was determined on MRA. RESULTS The patients exhibited significantly (p CONCLUSIONS The correlation between PCr on-kinetics and end-increment pH values might indicate remodelling processes within the muscle that probably affect mitochondrial performance, diffusion of oxygen, and muscle fiber distribution. These parameters could be improved by exercise training.
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NaHCO3-induced alkalosis reduces the phosphocreatine slow component during heavy-intensity forearm exercise.
Forbes, SC, Raymer, GH, Kowalchuk, JM, Marsh, GD
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(5):1668-75
Abstract
During heavy-intensity exercise, the mechanisms responsible for the continued slow decline in phosphocreatine concentration ([PCr]) (PCr slow component) have not been established. In this study, we tested the hypothesis that a reduced intracellular acidosis would result in a greater oxidative flux and, consequently, a reduced magnitude of the PCr slow component. Subjects (n = 10) performed isotonic wrist flexion in a control trial and in an induced alkalosis (Alk) trial (0.3g/kg oral dose of NaHCO3, 90 min before testing). Wrist flexion, at a contraction rate of 0.5 Hz, was performed for 9 min at moderate- (75% of onset of acidosis; intracellular pH threshold) and heavy-intensity (125% intracellular pH threshold) exercise. 31P-magnetic resonance spectroscopy was used to measure intracellular [H+], [PCr], [Pi], and [ATP]. The initial recovery data were used to estimate the rate of ATP synthesis and oxidative flux at the end of heavy-intensity exercise. In repeated trials, venous blood sampling was used to measure plasma [H+], [HCO3-], and [Lac-]. Throughout rest and exercise, plasma [H+] was lower (P < 0.05) and [HCO3-] was elevated (P < 0.05) in Alk compared with control. During the final 3 min of heavy-intensity exercise, Alk caused a lower (P < 0.05) intracellular [H+] [246 (SD 117) vs. 291 nmol/l (SD 129)], a greater (P < 0.05) [PCr] [12.7 (SD 7.0) vs. 9.9 mmol/l (SD 6.0)], and a reduced accumulation of [ADP] [0.065 (SD 0.031) vs. 0.098 mmol/l (SD 0.059)]. Oxidative flux was similar (P > 0.05) in the conditions at the end of heavy-intensity exercise. In conclusion, our results are consistent with a reduced intracellular acidosis, causing a decrease in the magnitude of the PCr slow component. The decreased PCr slow component in Alk did not appear to be due to an elevated oxidative flux.
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High-energy phosphate metabolism during two bouts of progressive calf exercise in humans measured by phosphorus-31 magnetic resonance spectroscopy.
Schocke, MF, Esterhammer, R, Arnold, W, Kammerlander, C, Burtscher, M, Fraedrich, G, Jaschke, WR, Greiner, A
European journal of applied physiology. 2005;(4):469-79
Abstract
According to the literature the steady-state level of phosphocreatine (PCr) has a linear relationship to the workload during muscle exercise intensities below the lactate threshold, whereas this linearity is impaired during exercise intensities above the lactate threshold. The purpose of this study was to investigate the linearity between PCr kinetics and workload during two bouts of isotonic incremental calf exercise with transitions from moderate- to high-intensity as well as from high- to moderate-intensity work rates. Using a whole-body 1.5 T MR scanner and a self-built exercise bench, we performed serial phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) with a time resolution of 30 s in nine healthy male volunteers. Changes in PCr, inorganic phosphate (Pi) and pH were statistically evaluated in comparison to the baseline. The exercise protocol started with a 4.5 W interval of 6 min followed by two bouts of 1.5 W increments. The workload was increased in 2-min intervals up to 9 W during the first bout and up to 7.5 W during the second bout. The second bout was preceded by a 4.5 W interval of 2 min and followed by a 4.5 W interval of 4 min. PCr hydrolysis achieved a steady state during each increment and was highly linear to the work rate (r (2), -0.796; P <0.001). Pi accumulated during each bout, whereas the pH decreased continuously during the first bout and did not exhibit any substantial decrease during the second bout. The metabolite levels and pH were expressed as the median value and the range. Our study confirms that steady-state PCr levels also have a linear relationship to work intensities above the lactate threshold, while pH changes do not have any impact on PCr degradation. The lack of substantial changes in pH during the second exercise bout indicates that prior high-intensity exercise leads to an activation of oxidative phosphorylation.