Creatine kinase and ATP synthase reaction rates in human frontal lobe measured by 31P magnetization transfer spectroscopy at 4T

Du, Fei; Cooper, Alissa J.; Lukas, Scott E.; Cohen, Bruce M.; Öngür, Döst

doi:10.1016/j.mri.2012.06.018

Cited by 22 publications

(23 citation statements)

References 36 publications

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“…b–b). The resultant T 1 , k , and σ parameters are consistent with the findings in human brains by long‐TR band inversion approaches and by ST , as compared in Table . Except for the ER matrix A (Eq.…”

Section: Discussionsupporting

confidence: 84%

Efficient ³¹P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T

Ren

Sherry

Malloy

2016

Magnetic Resonance in Med

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Purpose To develop an efficient 31P MRS method for measuring creatine kinase (CK) activity, ATP synthesis and motion dynamics in the human brain at 7T. Methods Three band inversion modules differing in center frequency were used to induce magnetization transfer (MT) effect in three exchange pathways 1) CK-mediated reaction PCr → γ-ATP; 2) de novo ATP synthesis Pi → γ-ATP; and 3) ATP intramolecular 31P-31P cross-relaxation γ-(α-) ↔ β-ATP. The resultant MT data were analyzed using a five-pool model in the format of magnetization matrix according to Bloch-McConnell-Solomon formalism. Results With repetition time TR 4 sec, the scan time for each module was ~8 min. The rate constants were kPCr→ γATP 0.38 ± 0.02 sec−1, kPi → γATP 0.19 ± 0.02 sec−1, and σγ(α) ↔ βATP − 0.19 ± 0.04 sec−1, correspond to ATP rotation correlation time τc (0.8 ± 0.2) ·10−7 sec. The T1 relaxation times were Pi 7.26 ± 1.76 sec, PCr 5.99 ± 0.58 sec, γ-ATP 0.98 ± 0.07 sec, α-ATP 0.95 ± 0.04 sec, and β-ATP 0.68 ± 0.03 sec. Conclusion Short-TR band inversion modules provide a time-efficient way of measuring brain ATP metabolism and could be useful in studying metabolic disorders in brain diseases.

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Section: Discussionsupporting

confidence: 84%

Efficient ³¹P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T

Ren

Sherry

Malloy

2016

Magnetic Resonance in Med

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“…31P-Magnetic resonance spectroscopy (31P-MRS) was used to measure brain ATP levels as described in previous studies 38–40 with modifications. Briefly, the mice under the control condition or isoflurane anesthesia were gently restrained to a plastic warm water bag (37 C°) in prone position, using paper tape.…”

Section: Methodsmentioning

confidence: 99%

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Wang¹,

Xu²,

et al. 2015

Anesthesia &Amp; Analgesia

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Background The mechanisms of general anesthesia by volatile drugs remain largely unknown. Mitochondrial dysfunction and reduction in energy levels have been suggested to be associated with general anesthesia status. 2-Deoxy-d-glucose (2-DG), an analog of glucose, inhibits hexokinase and reduces cellular levels of adenosine triphosphate (ATP). 3-Nitropropionic acid is another compound which can deplete ATP levels. In contrast, idebenone and L-carnitine could rescue deficits of energy. We therefore sought to determine whether 2-DG and/or 3-nitropropionic acid can enhance the anesthetic effects of isoflurane, and whether idebenone and L-carnitine can reverse the actions of 2-DG. Methods C57BL/6J mice (8 months old) received different concentrations of isoflurane with and without the treatments of 2-DG, 3-nitropropionic acid, idebenone, and L-carnitine. Isoflurane-induced loss of righting reflex (LORR) was determined in the mice. ATP levels in H4 human neuroglioma cells were assessed after these treatments. Finally, 31P-magnetic resonance spectroscopy was used to determine the effects of isoflurane on brain ATP levels in the mice. Results 2-DG enhanced isoflurane-induced LORR (P = 0.002, N = 15). 3-nitropropionic acid also enhanced the anesthetic effects of isoflurane (P = 0.005, N = 15). Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.165, N = 15), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P < 0.0001, N = 15), inhibited the effects of 2-DG on enhancing isoflurane-induced LORR in mice, as evidenced by 2-DG not enhancing isoflurane-induced LORR in mice pretreated with idebenone. Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.177, N = 6), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P = 0.029, N = 6), also mitigated the effects of 2-DG on reducing ATP levels in cells, as evidenced by 2-DG not decreasing ATP levels in the cell pretreated with idebenone. Finally, isoflurane decreased ATP levels in both cultured cells and mouse brains (-ATP: P = 0.003, N = 10; -ATP/phosphocreatine: P = 0.006, N = 10; -ATP/inorganic phosphate: P = 0.001, N = 10). Conclusions These results from our pilot studies have established a system and generated a hypothesis that 2-DG enhances anesthetic effects via reducing energy levels. These findings should promote further studies to investigate anesthesia mechanisms.

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“…In this work, we applied a BISTRO saturation scheme with significantly improved saturation profile . Previously, we demonstrated that the RF spillover effect is negligible during the use of the BISTRO saturation scheme with control spectrum acquired in the absence of RF saturation at 9.4T and 4T . Therefore, we believe only two 31 P spectra (control and saturation of γ‐ATP resonance) are required to determine forward reaction kinetics of CK/ATPases reactions in vivo at high/ultra‐high field scanner ( ≥ 4T).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo 31 P spectra were processed using the jMRUI software package (http://www.mrui.uab.es/mrui/mrui_Overview.shtml). The peak integrals of PCr, γ‐ATP, and Pi resonance were quantified by spectral fitting with the AMARES algorithm, as described in detail previously . All simulations in this study were performed using in‐house written MATLAB software (R2009b, Mathworks Inc, Natick, MA).…”

Section: Methodsmentioning

confidence: 99%

Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo

Kim

Chen

Öngür

et al. 2017

Magnetic Resonance Imaging

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Purpose: The metabolites phosphocreatine (PCr), adenosine triphosphate (ATP), and in-organic phosphate (Pi) are biochemically coupled. Their pool sizes, assessed by their magnetization ratios, have been extensively studied and reflect bioenergetics status in vivo. However, most such studies have ignored chemical exchange and T 1 relaxation effects. In this work, we aimed to extend the T nom 1 method to simultaneously quantify the reaction rate constants as well as phosphorus metabolite pool size ratios under partially relaxed conditions. Materials and Methods: Modified Bloch-McConnell equations were used to simulate the effects of chemical exchanges on T 1 relaxation times and magnetization ratios among PCr, c-ATP, and Pi. The T nom 1 method with iteration approach was used to measure both reaction constants and metabolite pool size ratios. To validate our method, in vivo data from rat brains (N 5 8) at 9.4 Tesla were acquired under two conditions, i.e., approximately full relaxation (TR 5 9 s) and partial relaxation (TR 5 3 s). We compared metabolite pool size ratios and reaction constants before and after correcting the chemical exchange and T 1 relaxation effects. Results: There were significant errors in underestimation of PCr/cATP by 12 % (P 5 0.03) and overestimation of ATP/Pi ratios by 14 % (P 5 0.04) when not considering chemical exchange effects. These errors were minimized using our iteration approach, resulting in no significant differences (PCr/cATP, P 5 0.47; ATP/Pi, P 5 0.81) in metabolite pool size ratios and reaction constants between the two measurements (i.e., short versus long TR conditions). Conclusion: Our method can facilitate broad biomedical applications of 31 P magnetization saturation transfer spectroscopy, requiring high temporal and/or spatial resolution for assessment of altered bioenergetics. P hosphorus magnetic resonance spectroscopy ( 31 P-MRS) provides insight into bioenergetic impairment and mitochondrial dysfunction in vivo under various physiological and pathological conditions. 1-5 Major phosphorus-containing metabolites related to bioenergetics detected by in vivo 31 P-MRS include phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) with the a-, b-, and c-resonances. These metabolites compose a chemical exchange network (PCr$ATP$Pi) catalyzed by the enzymes creatine kinase (CK) and ATP synthase (ATPase). These chemical reactions are crucial for regulating ATP metabolism and maintaining normal ATP functionality. The phosphorus metabolite levels or pool sizes assessed by their magnetization ratios such as PCr to c-ATP (PCr/c-ATP), c-ATP to Pi (c-ATP/Pi), and PCr to Pi (PCr/Pi) have been extensively studied in various disease states in vivo, for instance in the brain, 6-8 heart, 9,10 and muscle. 2,11 For measuring phosphorus-containing metabolite levels using a conventional MRS approach, Ernst and Anderson 12 suggested that large improvements in signal-to-noise ratio (SNR) per unit sampling time could be achieved by the use of short inter-pulse del...

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Creatine kinase and ATP synthase reaction rates in human frontal lobe measured by 31P magnetization transfer spectroscopy at 4T

Cited by 22 publications

References 36 publications

Efficient ³¹P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T

Efficient ³¹P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo

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Creatine kinase and ATP synthase reaction rates in human frontal lobe measured by 31P magnetization transfer spectroscopy at 4T

Cited by 22 publications

References 36 publications

Efficient 31P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T

Efficient 31P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo

Contact Info

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Efficient ³¹P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T

Efficient ³¹P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T