The importance of A TP as the main source of chemical energy in living matter and its involve­ ment in cellular processes has long been recog­ nized. The primary mechanism whereby higher or­ ganisms, including humans, generate ATP is through mitochondrial oxidative phosphorylation. For the majority of organs, the main metabolic fuel is glucose, which in the presence of oxygen under­ goes complete combustion to CO2 and H20: C6H1206 + 602 � 602 + 6H20 + energy ( 1) The free energy (.:lG) liberated in this exergonic re­ action is partially trapped as ATP in two consecu­ tive processes: glycolysis (cytosol) and oxidative phosphorylation (mitochondria). The first produces 2 mol of ATP per mol of glucose, and the second 36 mol of ATP per mol of glucose. In the latter case, 6 mol of ATP are contributed from the oxidation of 2 mol of NADH generated in the cytosol during gly­ colysis and transferred into the mitochondria indi­ rectly through various \"shuttle\" systems. (In the a-glycerophosphate shuttle, the yield of ATP per NADH is reduced from 3 to 2 because the relevant mitochondrial dehydrogenase is a flavoprotein­ linked enzyme). Thus, oxidative phosphorylation yields 1718 times as much useful energy in the form of ATP as can be obtained from the same amount of glucose by glycolysis alone. It is there­ fore not surprising that limitation of O2 supply pro­ duces very damaging effects on cellular function. The brain is one of the organs that is particularly sensitive to lack of oxygen and in humans at rest is responsible for 20% of total O2 consumption al­ though it accounts for only 2% of the body weight. The role of energy in the maintenance of central

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1989.2

ATP and brain function

The assumption that cellular oxygen pressure (PO2) is close to zero in maximally exercising muscle is essential for the hypothesis that O2 transport between blood and mitochondria has a finite conductance that determines maximum O2 consumption. The unique combination of isolated human quadriceps exercise, direct measures of arterial, femoral venous PO2, and 1H nuclear magnetic resonance spectroscopy to detect myoglobin desaturation enabled this assumption to be tested in six trained men while breathing room air (normoxic, N) and 12% O2 (hypoxic, H). Within 20 s of exercise onset partial myoglobin desaturation was evident even at 50% of maximum O2 consumption, was significantly greater in H than N, and was then constant at an average of 51 +/- 3% (N) and 60 +/- 3% (H) throughout the incremental exercise protocol to maximum work rate. Assuming a myoglobin PO2 where 50% of myoglobin binding sites are bound with O2 of 3.2 mmHg, myoglobin-associated PO2 averaged 3.1 +/- .3 (N) and 2.1 +/- .2 mmHg (H). At maximal exercise, measurements of arterial PO2 (115 +/- 4 [N] and 46 +/- 1 mmHg [H]) and femoral venous PO2 (22 +/- 1.6 [N] and 17 +/- 1.3 mmHg [H]) resulted in calculated mean capillary PO2 values of 38 +/- 2 (N) and 30 +/- 2 mmHg(H). Thus, for the first time, large differences in PO2 between blood and intracellular tissue have been demonstrated in intact normal human muscle and are found over a wide range of exercise intensities. These data are consistent with an O2 diffusion limitation across the 1-5-microns path-length from red cell to the sarcolemma that plays a role in determining maximal muscle O2 uptake in normal humans.

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Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport.

The literature describing 31P, 1H, 13C, 23Na and 19F MRS in vivo in human cancers is reviewed. Cancers have typical metabolic characteristics in 31P and 1H MRS including high levels of phospholipid metabolites and a cellular pH more alkaline than normal. These alone are not specific for cancer but are diagnostic in appropriate clinical settings. Some metabolic characteristics appear to be prognostic indices and correlation with treatment response is emerging as an important potentially cost-effective use of MRS in oncology. 19F MRS examines pharmacokinetics of 5-fluorouracil and by demonstrating its retention predicts response of a cancer to treatment. Current needs include improvement of diagnostic specificity by use of techniques like multivoxel MRS, proton decoupling of 31P, short echo time and fat-suppressed 1H MRS, 13C MRS direct or via 1H-observe, and statistical analysis of multiple spectral features. Trials in large populations in well defined clinical settings are needed to determine if MRS can provide independent prognostic indices useful in cancer management.

Studies of human tumors by MRS: a review.

Following the impetus of early clinical and experimental investigations, in vivo and in vitro MRS studies of tumours pointed in the eighties to the possible significance of signals arising from phospholipid (PL) precursors and catabolites as novel biochemical indicators of in vivo tumour progression and response to therapy. In the present decade, MRS analyses of individual components contributing to the 31P PME (phosphomonoester) and PDE (phosphodiester) resonances, as well as to the 1H 'choline peak', have reinforced some of these expectations. Moreover, the absolute quantification of these signals provided the basis for addressing more specific (although still open) questions on the biochemical mechanisms responsible for the formation of intracellular pools of PL derivatives in tumours, under different conditions of cell proliferative status and/or malignancy level. This article is aimed at providing an overview on: (a) quantitative MRS measurements on the contents of phosphocholine (PCho), phosphoethanolamine (PEtn) and their glycerol derivatives ģlycerol 3-phosphocholine (GPC) and glycerol 3-phosphoethanolamine (GPE)[ in human tumours and cells (with particular attention to breast and brain cancer and lymphomas), as well as in normal mammalian tissues (including developing organs and rapidly proliferating tissues); (b) possible correlations of MRS parameters like PEtn/PCho and PCho/GPC ratios with in vitro cell growth status and/or cell tumorigenicity; and (c) current and new hypotheses on the role and interplay of biosynthetic and catabolic pathways of the choline and ethanolamine cycles in modulating the intracellular sizes of PCho and PEtn pools, either in response to mitogenic stimuli or in relation to malignant transformation.

Tumour phospholipid metabolism.

Ions and energy in mammalian brain.

A new double-tuned probed for concurrent 1H and 31P NMR☆

Wireless implanted magnetic resonance probes for in vivo NMR

The in vivo dog brain 31P NMR spectrum has a large peak in the phosphodiester region accounting for more than 35% of the total observable phosphorus metabolites. It is possible to reduce the intensity of this peak by off-resonance saturation. To characterize the nature of this peak, extracts of dog brain frozen in situ were analyzed by high resolution 31P NMR. ATP, phosphocreatine, inorganic phosphate, and phosphomonoesters were recovered in appropriate amounts in the methanol:HCl extract. However, acid soluble phosphodiesters accounted for only 8% of the observable phosphorus. More NMR observable phosphodiesters were selectively recovered following CHCl3:methanol extraction of phospholipids. These results suggest that the in vivo phosphodiester resonance has substantial contributions from a fraction of mobile brain phospholipids.

31P NMR detection of mobile dog brain phospholipids.

Methods used to obtain and quantify high-quality time-resolved dog brain phosphorus nuclear magnetic resonance (31P NMR) spectra are described. In eight animals the normoxic dog brain spectra showed 10% of total phosphorus in ATP, 14% in phosphocreatine (PCr), and 38% in brain phospholipids containing phosphodiesters. The chemical shift between PCr and inorganic phosphate, 5.09, corresponded to an intracellular brain pH of 7.2. During hypoxia, PCr declined to 0.5 ± 0.3 (n = 8) of starting levels, prior to any changes in brain ATP. Simultaneous recording of the EEG was obtained in two animals. During hypoxia, progressive PCr depletion was associated with progressive slowing of the EEG, which was essentially silent before significant changes occurred in brain ATP. Finally, the brain 31P NMR spectrum and pH were measured at 90-s intervals, and the sequential changes that followed respiratory arrest were monitored in one dog until high-energy phosphate depletion was complete.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1984.50

In vivo Time-Resolved Brain Phosphorus Nuclear Magnetic Resonance

A multiple tuning NMR probe includes a radio frequency (RF) probe tuned by means of a circuit which creates a multiple pole circuit response in the probe, each of the poles being sufficiently separated from each other as to cause resonance of the probe at distinct frequencies. When tuning for nuclei with resonances substantially apart, this function may be accomplished using a parallel capacitor-inductor (L-C) trap with an impedance matching network. When tuning for nuclei with substantially closely spaced resonances, a tank circuit is used which has a single resonance which is split into two resonances by strongly coupling it to another tank circuit in resonance with the sample coil tank circuit.

V. Harihara Subramanian

Papers

A new double-tuned probed for concurrent 1H and 31P NMR☆

Wireless implanted magnetic resonance probes for in vivo NMR

31P NMR detection of mobile dog brain phospholipids.

In vivo Time-Resolved Brain Phosphorus Nuclear Magnetic Resonance

Multiple tuning NMR probe