Rate Of Oxidative Metabolism Research Articles

MTOR inhibition enhances synaptic and mitochondrial function in Alzheimer’s disease in an APOE genotype-dependent manner

Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer’s disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using in vivo 1H-[13C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.

Metabolic Remodeling during Early Cardiac Lineage Specification of Pluripotent Stem Cells.

Growing evidence indicates that metabolites and energy metabolism play an active rather than consequential role in regulating cellular fate. Cardiac development requires dramatic metabolic remodeling from relying primarily on glycolysis in pluripotent stem cells (PSCs) to oxidizing a wide array of energy substrates to match the high bioenergetic demands of continuous contraction in the developed heart. However, a detailed analysis of how remodeling of energy metabolism contributes to human cardiac development is lacking. Using dynamic multiple reaction monitoring metabolomics of central carbon metabolism, we evaluated temporal changes in energy metabolism during human PSC 3D cardiac lineage specification. Significant metabolic remodeling occurs during the complete differentiation, yet temporal analysis revealed that most changes occur during transitions from pluripotency to mesoderm (day 1) and mesoderm to early cardiac (day 5), with limited maturation of cardiac metabolism beyond day 5. Real-time metabolic analysis demonstrated that while hPSC cardiomyocytes (hPSC-CM) showed elevated rates of oxidative metabolism compared to PSCs, they still retained high glycolytic rates, confirming an immature metabolic phenotype. These observations support the opportunity to metabolically optimize the differentiation process to support lineage specification and maturation of hPSC-CMs.

Evaluation of Tibial Hemodynamic Response to Glucose Tolerance Test in Young Healthy Males and Females.

The relationship between glucose metabolism and bone health remains underexplored despite its clinical relevance. This study utilized the oral glucose tolerance test (OGTT) and near-infrared spectroscopy (NIRS) to probe gender-specific disparities in tibial hemodynamic responses among young healthy adults. Twenty-eight healthy participants (14 males) aged 18-28 years old were recruited for this study. After ingesting a 75 g glucose solution, tibial hemodynamic responses were captured using NIRS in combination with a 5 min ischemic reperfusion technique, both before and at 30 min intervals for two hours post-glucose ingestion. Parameters measured included oxidative metabolic rate (via tissue saturation index [TSI]), immediate recovery slope after occlusion release (TSI10), and total recovery magnitude (ΔTSI). Post-glucose ingestion, both genders demonstrated a surge in blood glucose concentrations at every time point compared to baseline (p < 0.001, 0.002, 0.009, and 0.039 for males; p < 0.001, < 0.001, = 0.002, and 0.017 for females). Baseline tibial metabolic rate, TSI10, and ΔTSI did not significantly differ between males and females (p = 0.734, 0.839, and 0.164, respectively), with no discernible temporal effects in any hemodynamic parameters within each gender (p = 0.864, 0.308, and 0.399, respectively, for males; p = 0.973, 0.453, and 0.137, respectively, for females). We found comparable tibial hemodynamic responses to OGTT between genders. This study demonstrated the utility of NIRS in evaluating tibial hemodynamic responses to glucose ingestion through OGTT, enriching our understanding of the body's metabolic responses to glucose intake.

Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease.

The energy demand of cardiomyocytes changes continuously in response to variations in cardiac workload. Cardiac excitation-contraction coupling is fueled primarily by adenosine triphosphate (ATP) production by oxidative phosphorylation in mitochondria. The rate of mitochondrial oxidative metabolism is matched to the rate of ATP consumption in the cytosol by the parallel activation of oxidative phosphorylation by calcium (Ca2+) and adenosine diphosphate (ADP). During cardiac workload transitions, Ca2+ accumulates in the mitochondrial matrix, where it stimulates the activity of the tricarboxylic acid cycle. In this review, we describe how mitochondria internalize and extrude Ca2+, the relevance of this process for ATP production and redox homeostasis in the healthy heart, and how derangements in ion handling cause mitochondrial and cardiomyocyte dysfunction in heart failure.

The fourth dimension: physiological resilience as an independent determinant of endurance exercise performance.

Endurance exercise performance is known to be closely associated with the three physiological pillars of maximal O2 uptake ( ), economy or efficiency during submaximal exercise, and the fractional utilisation of (linked to metabolic/lactate threshold phenomena). However, while 'start line' values of these variables are collectively useful in predicting performance in endurance events such as the marathon, it is not widely appreciated that these variables are not static but are prone to significant deterioration as fatiguing endurance exercise proceeds. For example, the 'critical power' (CP), which is a composite of the highest achievable steady-state oxidative metabolic rate and efficiency (O2 cost per watt), may fall by an average of 10% following 2h of heavy intensity cycle exercise. Even more striking is that the extent of this deterioration displays appreciable inter-individual variability, with changes in CP ranging from <1% to ∼32%. The mechanistic basis for such differences in fatigue resistance or 'physiological resilience' are not resolved. However, resilience may be important in explaining superlative endurance performance and it has implications for the physiological evaluation of athletes and the design of interventions to enhance performance. This article presents new information concerning the dynamic plasticity of the three 'traditional' physiological variables and argues that physiological resilience should be considered as an additional component, or fourth dimension, in models of endurance exercise performance.

Role of the ST6GAL1 sialyltransferase in regulating ovarian cancer cell metabolism.

The ST6GAL1 sialyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins, is upregulated in many malignancies including ovarian cancer. Through its activity in sialylating select surface receptors, ST6GAL1 modulates intracellular signaling to regulate tumor cell phenotype. ST6GAL1 has previously been shown to act as a survival factor that protects cancer cells from cytotoxic stressors such as hypoxia. In the present study, we investigated a role for ST6GAL1 in tumor cell metabolism. ST6GAL1 was overexpressed (OE) in OV4 ovarian cancer cells, which have low endogenous ST6GAL1, or knocked-down (KD) in ID8 ovarian cancer cells, which have high endogenous ST6GAL1. OV4 and ID8 cells with modulated ST6GAL1 expression were grown under normoxic or hypoxic conditions, and metabolism was assessed using Seahorse technology. Results showed that cells with high ST6GAL1 expression maintained a higher rate of oxidative metabolism than control cells following treatment with the hypoxia mimetic, desferrioxamine (DFO). This enrichment was not due to an increase in mitochondrial number. Glycolytic metabolism was also increased in OV4 and ID8 cells with high ST6GAL1 expression, and these cells displayed greater activity of the glycolytic enzymes, hexokinase and phosphofructokinase. Metabolism maps were generated from the combined Seahorse data, which suggested that ST6GAL1 functions to enhance the overall metabolism of tumor cells. Finally, we determined that OV4 and ID8 cells with high ST6GAL1 expression were more invasive under conditions of hypoxia. Collectively, these results highlight the importance of sialylation in regulating the metabolic phenotype of ovarian cancer cells.

Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo.

Uncoupling protein-3 (UCP3) is a mitochondrial transmembrane protein highly expressed in the muscle that has been implicated in regulating the efficiency of mitochondrial oxidative phosphorylation. Increasing UCP3 expression in skeletal muscle enhances proton leak across the inner mitochondrial membrane and increases oxygen consumption in isolated mitochondria, but its precise function in vivo has yet to be fully elucidated. To examine whether muscle-specific overexpression of UCP3 modulates muscle mitochondrial oxidation in vivo, rates of ATP synthesis were assessed by 31 P magnetic resonance spectroscopy (MRS), and rates of mitochondrial oxidative metabolism were measured by assessing the rate of [2-13 C]acetate incorporation into muscle [4-13 C]-, [3-13 C]-glutamate, and [4-13 C]-glutamine by high-resolution 13 C/1 H MRS. Using this approach, we found that the overexpression of UCP3 in skeletal muscle was accompanied by increased muscle mitochondrial inefficiency in vivo as reflected by a 42% reduction in the ratio of ATP synthesis to mitochondrial oxidation.

247.5: Magnetic Resonance Imaging of Renal Oxygen Metabolism by Means of 17-O Administration During Ex Vivo Organ Perfusion

Background: Renal normothermic machine perfusion (NMP) is a method studied for pre-transplant evaluation of kidney graft quality. This technique creates an isolated near-physiological environment by circulating a perfusion solution at body temperature with oxygen and nutrients. However, reliable ex vivo organ viability markers are still lacking. Magnetic resonance imaging (MRI) has recently been applied as a new rapid non-invasive technique to study renal viability ex vivo. Oxygen-17 (17O) offers a novel sensitive assessment of oxidative metabolism. In our MRI compatible perfusion setup, we aimed to study oxygen metabolism during NMP. Methods: Three viable porcine kidneys were retrieved at a slaughterhouse and preserved by oxygenated hypothermic machine perfusion. In addition, one discarded human kidney was shipped to our center in static cold storage. Subsequently each kidney was perfused for 4 hours at 37°C inside a clinical 3T MRI scanner. Blood gas, glucose, and electrolytes were periodically monitored. Anatomical T2-weighted images and T2* maps were obtained using a 1H 18Ch-bodyflex coil and dynamic radial 17O MR images were acquired using a 17O Tx/Rx loop coil and a 17O 3D-UTE sequence. The 17O perfusion protocol consisted of 4 minutes of deoxygenation with nitrogen gas, 8 minutes of 70%-enriched 17O2 gas infusion at 0.1L/min, and 20 minutes of subsequent carbogen (95% O2/ 5% CO2) oxygenation. 17O-magnitude data was analyzed dynamically over time. To study the 17O-related global signal change, a region of interest was defined in the anatomical T2-weighted images and co-registered to the dynamic 17O-magnitude data. Results: Porcine kidneys showed homogenous perfusion with increased H217O-concentration in the medulla and decreased concentration in the cortex. The discarded human kidney demonstrated a focused concentration in the medial side of the lower pole with little to no signal intensity in the upper pole and the majority of the cortex, which was consistent with its reason for discard (wide cist in the lateral pole). Six minutes after administration of 17O2-gas, a rapid H217O signal increase was observed until minute 20 of the dynamic acquisition, where saturation was reached and the signal plateaued. Overall, an enhancement of 16% between the first and last data point was measured. Conclusion: In these pilot experiments, we were able to quantify the regional production of H217O in time, both in porcine and human kidneys. The slope of occurrence of H217O may be an interesting ex vivo organ viability biomarker, immediately related to the rate of oxidative metabolism in the organ and hence organ quality. As the kidney is in an ex vivo setting, any increase in H217O-concentration must be the direct result of metabolism within the organ. The current setup has great potential for investigating renal oxygen metabolism ex vivo. NUKEM Isotopes GmbH, Alzenau, Germany. Department of Radiology, University Medical Center Freiburg, Freiburg, Germany.

Effects of Hydroxyurea on Skeletal Muscle Energetics and Function in a Mildly Anemic Mouse Model.

Hydroxyurea (HU) is a ribonucleotide reductase inhibitor most commonly used as a therapeutic agent in sickle cell disease (SCD) with the aim of reducing the risk of vaso-occlusion and improving oxygen transport to tissues. Previous studies suggest that HU may be even beneficial in mild anemia. However, the corresponding effects on skeletal muscle energetics and function have never been reported in such a mild anemia model. Seventeen mildly anemic HbAA Townes mice were subjected to a standardized rest-stimulation (transcutaneous stimulation)-protocol while muscle energetics using 31Phosphorus magnetic resonance spectroscopy and muscle force production were assessed and recorded. Eight mice were supplemented with hydroxyurea (HU) for 6 weeks while 9 were not (CON). HU mice displayed a higher specific total force production compared to the CON, with 501.35 ± 54.12 N/mm3 and 437.43 ± 57.10 N/mm3 respectively (+14.6%, p < 0.05). Neither the total rate of energy consumption nor the oxidative metabolic rate were significantly different between groups. The present results illustrated a positive effect of a HU chronic supplementation on skeletal muscle function in mice with mild anemia.

Constant power threshold—predicting maximal lactate steady state in recreational cyclists

IntroductionProlonged time trials proved capable of precisely estimating anaerobic threshold. However, time trial studies in recreational cyclists are missing. The aim of the present study was to evaluate accuracy and viability of constant power threshold, which is the highest power output constantly maintainable over time, for estimating maximal lactate steady state in recreational athletes.MethodsA total of 25 recreational athletes participated in the study of whom 22 (11 female, 11 male) conducted all constant load time trials required for determining constant power threshold 30 min and 45 min, which is the highest power output constantly maintainable over 30 min and 45 min, respectively. Maximal lactate steady state was assessed subsequently from blood samples taken every 5 min during the time trials.ResultsConstant power threshold over 45 min (175.5 ± 49.6 W) almost matched power output at maximal lactate steady state (176.4 ± 50.5 W), whereas constant power threshold over 30 min (181.4 ± 51.4 W) was marginally higher (P = 0.007, d = 0.74). Interrelations between maximal lactate steady state and constant power threshold 30 min and constant power threshold 45 min were very close (R2 = 0.99, SEE = 8.9 W, Percentage SEE (%SEE) = 5.1%, P < 0.001 and R2 = 0.99, SEE = 10.0 W, %SEE = 5.7%, P < 0.001, respectively).ConclusionsDetermination of constant power threshold is a straining but viable and precise alternative for recreational cyclists to estimate power output at maximal lactate steady state and thus maximal sustainable oxidative metabolic rate.

Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity.

HSPB5 or alpha B-crystallin (CRYAB), originally identified as lens protein, is one of the most widespread and represented of the human small heat shock proteins (sHSPs). It is greatly expressed in tissue with high rates of oxidative metabolism, such as skeletal and cardiac muscles, where HSPB5 dysfunction is associated with a plethora of human diseases. Since HSPB5 has a major role in protecting muscle tissues from the alterations of protein stability (i.e., microfilaments, microtubules, and intermediate filament components), it is not surprising that this sHSP is specifically modulated by exercise. Considering the robust content and the protective function of HSPB5 in striated muscle tissues, as well as its specific response to muscle contraction, it is then realistic to predict a specific role for exercise-induced modulation of HSPB5 in the prevention of muscle diseases caused by protein misfolding. After offering an overview of the current knowledge on HSPB5 structure and function in muscle, this review aims to introduce the reader to the capacity that different exercise modalities have to induce and/or activate HSPB5 to levels sufficient to confer protection, with the potential to prevent or delay skeletal and cardiac muscle disorders.

Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue

BackgroundIdiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment.MethodsAEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments.ResultsAEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs.ConclusionsThese results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.

BIMG-21. DEUTERIUM METABOLIC IMAGING (DMI), A NEW, MRI-BASED TECHNIQUE FOR MAPPING BRAIN TUMOR METABOLISM IN VIVO

Deuterium Metabolic Imaging (DMI) combines 3D deuterium (2H) magnetic resonance spectroscopic imaging (MRSI) with administration of a 2H-labeled substrate to map uptake and metabolism of the substrate. DMI has been implemented on a 4 Tesla clinical research MRI scanner, and on an 11.7 Tesla preclinical MRI scanner, and has been used with 2H-labeled glucose, acetate and choline. DMI data are presented as color maps of concentration of the 2H-labeled substrate and its metabolites, overlaid on anatomical MR images. In rat and mouse models of glioblastoma, DMI data acquired at 5 to 8 uL resolution following intravenous 2H-glucose infusion clearly showed the Warburg effect in the tumor lesions. The Warburg effect is indicated by the ratio of 2H-labeled lactate/glutamate+glutamine (Glx). High levels of 2H-labeled lactate and low levels of 2H-labeled Glx are the result of a high rate of glycolysis and low rate of oxidative glucose metabolism. Because DMI detects both glucose and its downstream metabolism, the technique does not suffer from low image contrast with normal brain, as is the case with FDG-PET that detects glucose uptake only. For clinical research studies patients orally consumed 0.75g/kg of 2H-glucose dissolved in water. The observations made in the animal models were confirmed in several patients with recurrent GBM, showing hotspots in the lac/Glx maps (8 mL resolution), coinciding with the area of the tumor lesion. In patients with meningioma, no Warburg effect was detected using DMI. Furthermore, DMI data acquired in a patient with GBM one week after finishing 30 days of radiation therapy, also showed no high levels of 2H-labeled lactate in the lesion. These data indicate that the presence of the Warburg effect could correlate with tumor grade and/or aggressiveness, and that DMI of glucose metabolism could potentially be a biomarker of therapy effect.

Glutamate-glutamine cycling and the oxidative metabolism rate in astrocytes

Glutamate-glutamine cycling and the oxidative metabolism rate in astrocytes

Hypoxia and Innate Immunity: Keeping Up with the HIFsters.

Recent years have witnessed an emergence of interest in understanding metabolic changes associated with immune responses, termed immunometabolism. As oxygen is central to all aerobic metabolism, hypoxia is now recognized to contribute fundamentally to inflammatory and immune responses. Studies from a number of groups have implicated a prominent role for oxygen metabolism and hypoxia in innate immunity of healthy tissue (physiologic hypoxia) and during active inflammation (inflammatory hypoxia). This inflammatory hypoxia emanates from a combination of recruited inflammatory cells (e.g., neutrophils, eosinophils, and monocytes), high rates of oxidative metabolism, and the activation of multiple oxygen-consuming enzymes during inflammation. These localized shifts toward hypoxia have identified a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of innate immunity. Such studies have provided new and enlightening insight into our basic understanding of immune mechanisms, and extensions of these findings have identified potential therapeutic targets. In this review, we summarize recent literature around the topic of innate immunity and mucosal hypoxia with a focus on transcriptional responses mediated by HIF.

The Effects of β-Hydroxy-β-Methylbutyrate (HMB) on Chemotaxis, Phagocytosis, and Oxidative Burst of Peripheral Blood Granulocytes and Monocytes in Goats.

Simple SummaryThe main focus of industrial livestock production is to maximise production output without compromising the well-being of animals, which is why animal diets are supplemented with various feed additives. Feed additives boost immunity and protect animals against pathogens. The list of potential feed additives includes β-hydroxy-β-methylbutyrate (HMB) which occurs naturally in small quantities in citrus fruit, avocado, asparagus, cauliflower, selected fish species, red wine, milk, and alfalfa. However, its mechanism of action and effects on immune system cells have not been thoroughly investigated in animals, including goats. In the present study, the experimental goats whose diets were supplemented with HMB over a period of 60 days were characterised by higher levels of chemotactic and phagocytic activity and a higher rate of oxidative metabolism of peripheral blood granulocytes and monocytes than control group animals whose diets were not supplemented. Granulocytes and monocytes constitute the first line of defence against pathogens and protect animals against disease. They play a particularly important role in young animals which are more susceptible to viral and bacterial infections. Feed additives can deliver numerous benefits by boosting immunity and preventing the spread of infectious diseases in goats.The objective of this study was to determine the effect of β-hydroxy-β-methylbutyrate (HMB) on the chemotactic activity, phagocytic activity, and oxidative metabolism of peripheral blood granulocytes and monocytes in goats. Goat kids aged 30 ± 3 days were divided into two groups of 12 animals each: I—control, and II—experimental. Experimental group animals were fed a diet supplemented with HMB in the amount of 50 mg/Kg BW; whereas the diets of control goats were not supplemented. At the beginning of the experiment (day 0) and on experimental days 15, 30, and 60, blood was sampled from the jugular vein to determine and compare chemotactic activity (MIGRATEST® kit), phagocytic activity (PHAGOTEST® kit), and oxidative metabolism (BURSTTEST® kit) of peripheral blood granulocytes and monocytes by flow cytometry. The analyses of the chemotactic and phagocytic activity of granulocytes and monocytes revealed statistically higher levels of phagocytic activity in the experimental group than in the control group, as expressed by the percentage of phagocytic cells and mean fluorescence intensity. HMB also enhanced the oxidative metabolism of both granulocytes and monocytes, expressed by the rate of oxidative metabolism and mean fluorescence intensity after stimulation with Escherichia coli bacteria and PMA (4-phorbol-12-β-myristate-13-acetate).

Antioxidant and Anticonvulsant Effect of Dennettia Tripetala on Rat Model of Isoniazid-induced Seizure

Aims: This study aimed at investigating the antioxidative, anticonvulsive and histological effects of ethanolic fruit extract of Dennettia tripetala on the pre-frontal lobe of the brain in isoniazid-induced (300 mg/kg, i.p) seizure in adult wistar rat.&#x0D; Introduction: Neuronal hyper-excitability and excessive production of free radicals have been implicated in the pathogenesis of a considerable range of neurological disorders, including epilepsy. The high rate of oxidative metabolism, coupled with the low antioxidant defenses and the richness in polyunsaturated fatty acids, makes the brain highly vulnerable to free radical damage.&#x0D; Study Design: This is an original research conducted in Department of Anatomy, Faculty of Basic Medical Sciences, Enugu State University of Science and Technology (ESUT), Parklane, Enugu State, Nigeria, between June and August, 2019.&#x0D; Methodology: A total number of twenty four wistar rats were used for this experiment, the animals were grouped into six groups with four animals per group, Group I served as the negative control, Group II served as the positive control, Group III received the standard drug as well as the Isoniazid, while group IV, V and VI were treated with ethanolic extract of Dennettia tripetala at different dosages; 250 mg/kg, 500 mg/kg and 750 mg/kg, intraperitoneally (i.p) respectively and its effects compared with a standard drug (Pyridoxine) treated group.&#x0D; Results: The extract significantly prolonged the onset of seizure at high dose administration (750 mg/kg) but completely prevented seizure occurrence at low and medium dose administration (250 mg/kg and 500 mg/kg, i.p) when induced with isoniazid (300 mg/kg, i.p.).&#x0D; Conclusion: The results obtained from this work suggest that ethanolic extract of Dennettia tripetala has anticonvulsant activity, and this supports the use of the formulation traditionally in the treatment of convulsions, thus should be considered for clinical trials.

Metabolic Profiling Using Stable Isotope Tracing Reveals Distinct Patterns of Glucose Utilization by Physiologically Activated CD8+ T Cells

Naive CD8+ Tcells differentiating into effector Tcells increase glucose uptake and shift from quiescent to anabolic metabolism. Although much is known about the metabolism of cultured Tcells, how Tcells use nutrients during immune responses invivo is less well defined. Here, we combined bioenergetic profiling and 13C-glucose infusion techniques to investigate the metabolism of CD8+ Tcells responding to Listeria infection. In contrast to invitro-activated Tcells, which display hallmarks of Warburg metabolism, physiologically activated CD8+ Tcells displayed greater rates of oxidative metabolism, higher bioenergetic capacity, differential use of pyruvate, and prominent flow of 13C-glucose carbon to anabolic pathways, including nucleotide and serine biosynthesis. Glucose-dependent serine biosynthesis mediated by the enzyme Phgdh was essential for CD8+ Tcell expansion invivo. Our data highlight fundamental differences in glucose use by pathogen-specific Tcells invivo, illustrating the impact of environment on Tcell metabolic phenotypes.

The maximal metabolic steady state: redefining the 'gold standard'.

The maximal lactate steady state (MLSS) and the critical power (CP) are two widely used indices of the highest oxidative metabolic rate that can be sustained during continuous exercise and are often considered to be synonymous. However, while perhaps having similarities in principle, methodological differences in the assessment of these parameters typically result in MLSS occurring at a somewhat lower power output or running speed and exercise at CP being sustainable for no more than approximately 20–30 min. This has led to the view that CP overestimates the ‘actual’ maximal metabolic steady state and that MLSS should be considered the ‘gold standard’ metric for the evaluation of endurance exercise capacity. In this article we will present evidence consistent with the contrary conclusion: i.e., that (1) as presently defined, MLSS naturally underestimates the actual maximal metabolic steady state; and (2) CP alone represents the boundary between discrete exercise intensity domains within which the dynamic cardiorespiratory and muscle metabolic responses to exercise differ profoundly. While both MLSS and CP may have relevance for athletic training and performance, we urge that the distinction between the two concepts/metrics be better appreciated and that comparisons between MLSS and CP, undertaken in the mistaken belief that they are theoretically synonymous, is discontinued. CP represents the genuine boundary separating exercise in which physiological homeostasis can be maintained from exercise in which it cannot, and should be considered the gold standard when the goal is to determine the maximal metabolic steady state.

Informative changes in indicators of homeostasis to the assessment of individual risk adaptation disorders in workers of the chemical industry.

This paper reviews the results of complex laboratory examinations among workers manufacturing fiber glass. The most pronounced and early changes in oxidative metabolism processes (reduced catalase activity, increased malonic dialdehyde) and rates of blood serum lipid metabolism indicators were determined, increased values of leukocyte indices of intoxication, violations in the immune status. Changes were detected in workers even with a small length of service (5 years) and young age (20-30 years). With increasing length of service in the workplace, the frequency of these violations increased.Based on the data obtained we have developed laboratory markers that are suitable for diagnosing early preclinical disorders among fiber glass manufacturing workers.