Interpretation of31P NMR saturation transfer experiments: what you can't see might confuse you. Focus on “Standard magnetic resonance-based measurements of the Pi→ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles”

Balaban, Robert S.; Koretsky, Alan P.

doi:10.1152/ajpcell.00100.2011

Cited by 40 publications

(52 citation statements)

References 40 publications

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“…In addition to putative contributions from exchange via GAPDH/PGK (45) and at the mitochondrion, Balaban and Koretsky (46) suggest that small metabolite pools, undetectable in the 31 P-MR spectrum due to their low concentration, could be irradiated during the ST experiment, undergo exchange with P i , and contribute to the observed MT effect. These concerns are certainly valid in terms of deconvoluting the specific mechanisms that contribute to the P i → ATP flux and quantifying absolute rates of net (i.e., forward flux minus reverse flux) mitochondrial ATP synthesis.…”

Section: Influence Of Near-equilibrium Pi ⇆ Atp Exchange On In Vivo Smentioning

confidence: 99%

31P-Magnetization Transfer Magnetic Resonance Spectroscopy Measurements of In Vivo Metabolism

et al. 2012

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Magnetic resonance spectroscopy offers a broad range of noninvasive analytical methods for investigating metabolism in vivo. Of these, the magnetization-transfer (MT) techniques permit the estimation of the unidirectional fluxes associated with metabolic exchange reactions. Phosphorus (31P) MT measurements can be used to examine the bioenergetic reactions of the creatine-kinase system and the ATP synthesis/hydrolysis cycle. Observations from our group and others suggest that the inorganic phosphate (Pi) → ATP flux in skeletal muscle may be modulated by certain conditions, including aging, insulin resistance, and diabetes, and may reflect inherent alterations in mitochondrial metabolism. However, such effects on the Pi → ATP flux are not universally observed under conditions in which mitochondrial function, assessed by other techniques, is impaired, and recent articles have raised concerns about the absolute magnitude of the measured reaction rates. As the application of 31P-MT techniques becomes more widespread, this article reviews the methodology and outlines our experience with its implementation in a variety of models in vivo. Also discussed are potential limitations of the technique, complementary methods for assessing oxidative metabolism, and whether the Pi → ATP flux is a viable biomarker of metabolic function in vivo.

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Section: Influence Of Near-equilibrium Pi ⇆ Atp Exchange On In Vivo Smentioning

confidence: 99%

31P-Magnetization Transfer Magnetic Resonance Spectroscopy Measurements of In Vivo Metabolism

et al. 2012

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“…However, the use of long saturation pulses may not always be practical on clinical scanners. Further, the underlying mechanisms of some ST effects are still being debated (12,17,125,126). Several studies have used inversion transfer (IT) to quantify exchange kinetics (127-129).…”

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confidence: 99%

Assessing tissue metabolism by phosphorous-31 magnetic resonance spectroscopy and imaging: a methodology review

Liu

2017

Quant. Imaging Med. Surg.

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Many human diseases are caused by an imbalance between energy production and demand.Magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide the unique opportunity for in vivo assessment of several fundamental events in tissue metabolism without the use of ionizing radiation. Of particular interest, phosphate metabolites that are involved in ATP generation and utilization can be quantified noninvasively by phosphorous-31 ( 31 P) MRS/MRI. Furthermore, 31 P magnetization transfer (MT) techniques allow in vivo measurement of metabolic fluxes via creatine kinase (CK) and ATP synthase. However, a major impediment for the clinical applications of 31 P-MRS/MRI is the prohibitively long acquisition time and/or the low spatial resolution that are necessary to achieve adequate signal-to-noise ratio. P-MRS/MRI techniques. Applications of these techniques to the investigation of a specific physiology/pathology will be discussed without detailed description. Interested readers are referred to recent review articles on the applications of 31 P-MRS/MRI in metabolic characterization of skeletal muscle (10-12), heart (13), brain (14), and liver (11), as well as in diseases such as cancer (15), heart failure (16), and obesity and diabetes (17,18). Historical perspectiveThe use of 31 P-MRS for metabolic investigations dates back to 1960. Cohn and Hughes were the first to obtain a high-resolution 31 P spectrum of a solution of ATP (19). In addition, they also observed a dependence of the chemical shifts of the phosphorus nuclei of ATP on the pH of the solution. In parallel to the early development of MRI methods by Lauterbur (20), the entire 1970s also witnessed the rapid advance of 31 P-MRS in metabolic investigation of a broad range of biological systems. In 1973, Moon and Richards performed the first 31 P-MRS study that measured intracellular pH in human red blood cells (21). In the following year, Henderson and colleagues obtained the first 31 P spectrum of ATP from human red blood cells (22). At the same time, the Oxford team led by Radda performed the first experiment to acquire 31 P spectra from an intact organ, i.e., the excised and superfused muscle of rat hindlimb (23). The first in vivo 31 P-MRS study was performed on mouse brain by Chance et al. (24). Within the short span of one decade, organelles including mitochondria (25,26) and chromaffin granules (27), cells including Escherichia coli (28), yeast (29), and hepatocytes (30), and organs including skeletal muscle (31,32), heart (33-35), brain (36), kidney (37), and liver (38,39) have all been studied using 31 P-MRS.It is worth noting that most of these organ studies were performed on excised organs to avoid the need for spatial localization. Although Lauterbur has demonstrated the feasibility of imaging water protons (20), it was considered impractical for 31 P imaging of living systems because of the low sensitivity and difficulties with spectral resolution.The 1980s began with the publication of two important studies that aimed a...

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“…P i →ATP flux) represent the sum of all ATP synthesis reactions involving P i through both glycolysis and mitochondrial oxidative phosphorylation (OxPhos), but this is dominated by glyoclytically mediated Pi-ATP exchange (Kemp 2008;Balaban and Koretsky 2011;From and Ugurbil 2011;Kemp and Brindle 2012). An approximately 55% decline in P i →ATP flux in IL10 tm/tm mice was observed and this lower unidirectional P i →ATP flux was not due to substrate driving the reaction since P i was higher, not lower, in IL10 tm/tm mice.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle ATP kinetics are impaired in frail mice

Akki

Yang

Gupta

et al. 2013

AGE

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The interleukin-10 knockout mouse (IL10 tm/tm ) has been proposed as a model for human frailty, a geriatric syndrome characterized by skeletal muscle (SM) weakness, because it develops an age-related decline in SM strength compared to control (C57BL/6J) mice. Compromised energy metabolism and energy deprivation appear to play a central role in muscle weakness in metabolic myopathies and muscular dystrophies. Nonetheless, it is not known whether SM energy metabolism is altered in frailty. A combination of in vivo 31 P nuclear magnetic resonance experiments and biochemical assays was used to measure high-energy phosphate concentrations, the rate of ATP synthesis via creatine kinase (CK), the primary energy reserve reaction in SM, as well as the unidirectional rates of ATP synthesis from inorganic phosphate (P i ) in hind limb SM of 92-week-old control (n=7) and IL10 tm/tm (n=6) mice. SM Phosphocreatine (20.2±2.3 vs. 16.8± 2.3 μmol/g, control vs. IL10 tm/tm , p<0.05), ATP flux via CK (5.0±0.9 vs. 3.1±1.1 μmol/g/s, p<0.01), ATP synthesis from inorganic phosphate (P i →ATP) (0.58±0.3 vs. 0.26±0.2 μmol/g/s, p<0.05) and the free energy released from ATP hydrolysis (ΔG ∼ATP ) were significantly lower and [P i ] (2.8±1.0 vs. 5.3± 2.0 μmol/g, control vs. IL10 tm/tm , p<0.05) markedly higher in IL10 tm/tm than in control mice. These observations demonstrate that, despite normal in vitro metabolic enzyme activities, in vivo SM ATP kinetics, high-energy phosphate levels and energy release from ATP hydrolysis are reduced and inorganic phosphate is elevated in a murine model of frailty. These observations do not prove, but are consistent with the premise, that energetic abnormalities may contribute metabolically to SM weakness in this geriatric syndrome.

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Interpretation of³¹P NMR saturation transfer experiments: what you can't see might confuse you. Focus on “Standard magnetic resonance-based measurements of the P_i→ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles”

Abstract: Interpretation of P NMR saturation transfer experiments: what you can't see might confuse you.Focus on "Standard magnetic resonance-based measurements of the P i ¡ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles"

Cited by 40 publications

References 40 publications

31P-Magnetization Transfer Magnetic Resonance Spectroscopy Measurements of In Vivo Metabolism

31P-Magnetization Transfer Magnetic Resonance Spectroscopy Measurements of In Vivo Metabolism

Assessing tissue metabolism by phosphorous-31 magnetic resonance spectroscopy and imaging: a methodology review

Skeletal muscle ATP kinetics are impaired in frail mice

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