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      In vivo assessment of β‐hydroxybutyrate metabolism in mouse brain using deuterium ( 2H) MRS

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          Abstract

          Purpose

          To monitor the metabolic turnover of β‐hydroxybutyrate (BHB) oxidation using 2H‐MRS in conjunction with intravenous administration of 2H labeled BHB.

          Methods

          Nine‐month‐old mice were infused with [3,4,4,4]‐ 2H 4‐BHB (d 4‐BHB; 3.11 g/kg) through the tail vein using a bolus variable infusion rate for a period of 90 min. The labeling of downstream cerebral metabolites from the oxidative metabolism of d 4‐BHB was monitored using 2H‐MRS spectra acquired with a home‐built 2H surface coil on a 9.4T preclinical MR scanner with a temporal resolution of 6.25 min. An exponential model was fit to the BHB and glutamate/glutamine (Glx) turnover curves to determine rate constants of metabolite turnover and to aid in the visualization of metabolite time courses.

          Results

          Deuterium label was incorporated into Glx from BHB metabolism through the tricarboxylic acid (TCA) cycle, with an increase in the level of [4,4]‐ 2H 2‐Glx (d 2‐Glx) over time and reaching a quasi‐steady state concentration of ∼0.6 ± 0.1 mM following 30 min of infusion. Complete oxidative metabolic breakdown of d 4‐BHB also resulted in the formation of semi‐heavy water (HDO), with a four‐fold (10.1 to ∼42.1 ± 7.3 mM) linear (R 2 = 0.998) increase in its concentration by the end of infusion. The rate constant of Glx turnover from d 4‐BHB metabolism was determined to be 0.034 ± 0.004 min −1.

          Conclusion

          2H‐MRS can be used to monitor the cerebral metabolism of BHB with its deuterated form by measuring the downstream labeling of Glx. The integration of 2H‐MRS with deuterated BHB substrate provides an alternative and clinically promising MRS tool to detect neurometabolic fluxes in healthy and disease conditions.

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          Most cited references37

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          Cellular energy utilization and molecular origin of standard metabolic rate in mammals.

          The molecular origin of standard metabolic rate and thermogenesis in mammals is examined. It is pointed out that there are important differences and distinctions between the cellular reactions that 1) couple to oxygen consumption, 2) uncouple metabolism, 3) hydrolyze ATP, 4) control metabolic rate, 5) regulate metabolic rate, 6) produce heat, and 7) dissipate free energy. The quantitative contribution of different cellular reactions to these processes is assessed in mammals. We estimate that approximately 90% of mammalian oxygen consumption in the standard state is mitochondrial, of which approximately 20% is uncoupled by the mitochondrial proton leak and 80% is coupled to ATP synthesis. The consequences of the significant contribution of proton leak to standard metabolic rate for tissue P-to-O ratio, heat production, and free energy dissipation by oxidative phosphorylation and the estimated contribution of ATP-consuming processes to tissue oxygen consumption rate are discussed. Of the 80% of oxygen consumption coupled to ATP synthesis, approximately 25-30% is used by protein synthesis, 19-28% by the Na(+)-K(+)-ATPase, 4-8% by the Ca2(+)-ATPase, 2-8% by the actinomyosin ATPase, 7-10% by gluconeogenesis, and 3% by ureagenesis, with mRNA synthesis and substrate cycling also making significant contributions. The main cellular reactions that uncouple standard energy metabolism are the Na+, K+, H+, and Ca2+ channels and leaks of cell membranes and protein breakdown. Cellular metabolic rate is controlled by a number of processes including metabolic demand and substrate supply. The differences in standard metabolic rate between animals of different body mass and phylogeny appear to be due to proportionate changes in the whole of energy metabolism. Heat is produced by some reactions and taken up by others but is mainly produced by the reactions of mitochondrial respiration, oxidative phosphorylation, and proton leak on the inner mitochondrial membrane. Free energy is dissipated by all cellular reactions, but the major contributions are by the ATP-utilizing reactions and the uncoupling reactions. The functions and evolutionary significance of standard metabolic rate are discussed.
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            Appraising the brain's energy budget.

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              Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.

              Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Abeta) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Abeta binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.
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                Author and article information

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                Journal
                Magnetic Resonance in Medicine
                Magnetic Resonance in Med
                Wiley
                0740-3194
                1522-2594
                July 2023
                March 27 2023
                July 2023
                : 90
                : 1
                : 259-269
                Affiliations
                [1 ] Department of Radiology, Center for Advanced Metabolic Imaging in Precision Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA
                [2 ] Department of Bioengineering, School of Engineering and Applied Sciences University of Pennsylvania Philadelphia Pennsylvania United States
                [3 ] Department of Psychiatry, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania United States
                [4 ] Department of Neurology, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania United States
                Article
                10.1002/mrm.29648
                36971349
                94be76b1-d1c1-46ab-ad86-d09b368f9624
                © 2023

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