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At least 91 records · Page 5
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Seven days of ischemic preconditioning augments hypoxic exercise ventilation and muscle oxygenation in recreationally trained males

This investigation sought to assess whether single or repeated bouts of ischemic preconditioning (IPC) could improve oxyhemoglobin saturation ([Formula: see text]) and/or attenuate reductions in muscle tissue saturation index (TSI) during submaximal hypoxic exercise. Fifteen healthy young men completed submaximal graded exercise under four experimental conditions: 1) normoxia (NORM), 2) hypoxia (HYP) [oxygen fraction of inspired air ([Formula: see text]) = 0.14, ∼3,200 m], 3) hypoxia preceded by a single session of IPC (IPC1-HYP), and 4) hypoxia preceded by seven sessions of IPC, one a day for 7 consecutive days (IPC7-HYP). IPC7-HYP heightened minute ventilation (V̇e) at 80% HYP peak cycling power output ( W peak ) (+10.47 ± 3.35 L·min −1 , P = 0.006), compared with HYP, as a function of increased breathing frequency. Both IPC1-HYP (+0.17 ± 0.04 L·min −1 , P < 0.001) and IPC7-HYP (+0.16 ± 0.04 L·min −1 , P < 0.001) elicited greater oxygen consumption (V̇o 2 ) across exercise intensities compared with NORM, whereas V̇o 2 was unchanged with HYP alone. [Formula: see text] was unchanged by either IPC condition at any exercise intensity, yet the reduction of muscle TSI during resting hypoxic exposure was attenuated by IPC7-HYP (+9.9 ± 3.6%, P = 0.040) compared with HYP, likely as a function of reduced local oxygen extraction. Considering all exercise intensities, IPC7-HYP attenuated reductions of TSI with HYP (+6.4 ± 1.8%, P = 0.001). Seven days of IPC heightens ventilation, posing a threat to ventilatory efficiency, during high-intensity submaximal hypoxic exercise and attenuates reductions in hypoxic resting and exercise muscle oxygenation in healthy young men. A single session of IPC may be capable of modulating hypoxic ventilation; however, our present population was unable to demonstrate this with certainty.

Physiology↗
NASA NTRS1975

Metabolic rate control during extravehicular activity simulations and measurement techniques during actual EVAS

A description of the methods used to control and measure metabolic rate during ground simulations is given. Work levels attained at the Space Environment Simulation Laboratory are presented. The techniques and data acquired during ground simulations are described and compared with inflight procedures. Data from both the Skylab and Apollo Program were utilized and emphasis is given to the methodology, both in simulation and during flight. The basic techniques of work rate assessment are described. They include oxygen consumption, which was useful for averages over long time periods, heart rate correlations based on laboratory calibrations, and liquid cooling garment temperature changes. The relative accuracy of these methods as well as the methods of real-time monitoring at the Mission Control Center are discussed. The advantages and disadvantages of each of the metabolic measurement techniques are discussed. Particular emphasis is given to the problem of utilizing oxygen decrement for short time periods and heart rate at low work levels. A summary is given of the effectiveness of work rate control and measurements; and current plans for future EVA monitoring are discussed.

David J. Horrigan↗
NASA NTRS2002

Oxidation Behavior of GRCop-84 Copper Alloy Assessed

NASA's goal of safe, affordable space transportation calls for increased reliability and lifetimes of launch vehicles, and significant reductions of launch costs. The areas targeted for enhanced performance in the next generation of reusable launch vehicles include combustion chambers and nozzle ramps; therefore, the search is on for suitable liner materials for these components. GRCop-84 (Cu-8Cr-4Nb), an advanced copper alloy developed at the NASA Glenn Research Center in conjunction with Case Western Reserve University, is a candidate. The current liner of the Space Shuttle Main Engine is another copper alloy, NARloy-Z (Cu-3Ag-0.1Zr). It provides a benchmark against which to compare the properties of candidate successors. The thermomechanical properties of GRCop-84 have been shown to be superior, and its physical properties comparable, to those of NARloy-Z. However, environmental durability issues control longevity in this application: because copper oxide scales are not highly protective, most copper alloys are quickly consumed in oxygen environments at elevated temperatures. In consequence, NARloy-Z and most other copper alloys are prone to blanching, a degradation process that occurs through cycles of oxidation-reduction as the oxide is repeatedly formed and removed because of microscale fluctuations in the oxygen-hydrogen fuel systems of rocket engines. The Space Shuttle Main Engine lining typically degraded by blanching-induced hot spots that lead to surface roughening, pore formation, and coolant leakage. Therefore, resistance to oxidation and blanching are key requirements for second-generation reusable launch vehicle liners. The rocket engine ambient includes H2 (fuel) and H2O (combustion product) and is, hence, under reduced oxygen partial pressures. Accordingly, our studies were expanded to include oxygen partial pressures as low as 322 parts per million (ppm) at the temperatures likely to be experienced in service. A comparison of 10-hr weight gains of GRCop-84, NARloy-Z, and pure copper in 0.032, 2.2, and 100 percent oxygen from 550 to 750 C is shown. In 2.2 vol% and higher oxygen content, GRCop-84 oxidation was slower than that of NARloy-Z or Cu, but that advantage was lost or diminished in 322-ppm O2. Over longer (50-hr) exposures in 1.0 atm O2, however, the advantage of GRCop-84 increased significantly, its oxidation rate becoming approximately 10 times slower than those of Cu and NARloy-Z from 500 to 700 C. Weight gains were moderate and the kinetics parabolic for all three materials in 2.2 vol% and higher oxygen content; however, in 322-ppm O2, the scales were nonprotective below about 650 C, as reflected in linear kinetics and large weight gains. The superior oxidation resistance of GRCop-84 is likely related to the kinetics of extra oxygen consumption to form the additional oxides of Cr and Nb detected beneath the GRCop-84 oxide layer. While we continue to evaluate the blanching resistance of GRCop-84 in other tests, these oxidation results indicate that GRCop-84 is suitable as a reusable launch vehicle liner, and in applications where it is desired to use a copper alloy but without the risk of oxidative failure. Three bar charts comparing overall specific weight gains by each of the three materials studied. The top chart is for oxidation in 1.0 atm of oxygen, the middle is for 2.2% oxygen (balance argon), and the bottom is for 0.0322% oxygen. GRCop-84 outperforms the other two materials, showing the least weight gain in nearly all cases.

Thomas-Ogbuji, Linus U.↗
NASA NTRS1971

Metabolic effects of artificial environments

The mechanisms by which inert gases influence metabolism were investigated from several viewpoints. Groups of rats were exposed at the thermal neutral temperature of the respective mixtures, to normoxic (P sub A 02 = 100 mm Hq) environments with argon, helium or nitrogen as the diluent at a total pressure of one atmosphere. The possible influence of diluent gases on oxygen transport to the cell was examined with hypoxic (P sub A O2 = 70 mm Hg) mixtures of the same diluent gases. Metabolic measurements included food, water, and oxygen consumption, CO2 production, hematocrit and the rate C-14O2 of expiration subsequent to intraperitoneal injection of acetate-1-C-14 or glucose UL-C-14. Argon-exposed animals showed a consistently decreased metabolic rate while, on the other hand, helium-exposed rats did not significantly alter metabolic rate relative to nitrogen. Certain indices, including acetate and glucose utilization, suggested that helium attenuated the imposed hypoxia at the cellular level while argon facilitated it as compared with nitrogen. These results suggest that metabolic influence of helium is largely thermal in nature while argon has a significant direct metabolic effect and that diluent gases may selectively influence oxygen availability to the interior of the cell.

Jordan, J. P.↗
DOE OSTI2021

SMYD2 suppresses p53 activity to promote glucose metabolism in cervical cancer

Reprogrammed energy metabolism, especially the Warburg effect, is emerged as a hallmark of cancer. The protein lysine methyltransferase SMYD2 functions as an oncogene and is implicated in various malignant phenotypes of human cancers. However, the role of SMYD2 in tumor metabolism is still largely unknown. Here, we report that SMYD2 is highly expressed in human cervical cancer and its aberrant expression is linked to a poor prognosis. Bioinformatic analysis revealed a novel link between SMYD2 expression and aerobic glycolysis. Through loss-of-function experiments, we demonstrated that SMYD2 knockdown or inhibition induced a metabolic shift from aerobic glycolysis to oxidative phosphorylation, as evidenced by glucose uptake, lactate production, extracellular acidification, and the oxygen consumption rate. In contrast, SMYD2 overexpression promoted glycolytic metabolism in cervical cancer cells. Moreover, SMYD2 was required for tumor growth in cervical cancer and this oncogenic activity was largely glycolysis-dependent. Mechanistically, SMYD2 altered the methylation status of p53 and inhibited its transcriptional activity. Genetic silencing of p53 largely abrogated the effects of SMYD2 in promoting aerobic glycolysis. Taken together, our findings reveal a novel function of SMYD2 in regulating the Warburg effect in cervical cancer.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2010

NIRS-Derived Tissue Oxygen Saturation and Hydrogen Ion Concentration Following Bed Rest

Long-term bed rest (BR), a model of spaceflight, results in a decrease in aerobic capacity and altered submaximal exercise responses. The strongest BR-induced effects on exercise appear to be centrally-mediated, but longer BR durations may result in peripheral adaptations (e.g., decreased mitochondrial and capillary density) which are likely to influence exercise responses. PURPOSE: To measure tissue oxygen saturation (SO2) and hydrogen ion concentration ([H+]) in the vastus lateralis (VL) using near infrared spectroscopy (NIRS) during cycle ergometry before and after . 30 d of BR. METHODS: Eight subjects performed a graded exercise test on a cycle ergometer to volitional fatigue 7 d before (pre-BR) and at the end or 1 day after BR (post-BR). NIRS spectra were collected from a sensor adhered to the skin overlying the VL. Oxygen consumption (VO2) was measured by open circuit spirometry. Blood volume (BV) was measured before and after BR using the carbon monoxide rebreathing technique. Changes in pre- and post-BR SO2 and [H+] data were compared using mixed model analyses. BV and peak exercise data were compared using paired t-tests. RESULTS: BV (pre-BR: 4.3+/-0.3, post-BR: 3.7+/-0.2 L, mean+/-SE, p=.01) and peak VO2 (pre-BR: 1.98+/-0.24, post-BR: 1.48 +/-0.21 L/min, p<.01) were reduced after BR. As expected, SO2 decreased with exercise before and after BR. However, SO2 was lower post compared with pre-BR throughout exercise, including at peak exercise (pre-BR: 50+/-3, post-BR: 43+/-4%, p=.01). After BR, [H+] was higher at the start of exercise and did not increase at the same rate as pre-BR. Peak [H+] was not different from pre to post-BR (pre-BR: 36+/-2; post-BR: 38+/-2 nmol/L). CONCLUSIONS: Lower SO2 during exercise suggests that oxygen extraction in the VL is higher after BR, perhaps due to lower circulating blood volume. The higher [H+] after BR suggests a greater reliance upon glycolysis during submaximal exercise, although [H+] at peak exercise was unchanged. Taken together, these data suggest that longer duration BR induces a number of changes that result in peripheral adaptations which contribute to cardiovascular and muscular deconditioning as measured by NIRS-derived SO2 and [H+] in the VL and may contribute to lower post-BR exercise tolerance. Supported by the National Space Biomedical Research Institute through NASA NCC 9-58

Lee, S. M. C.↗
NASA NTRS1993

Effect of exercise training on cardiopulmonary baroreflex control of forearm vascular resistance in humans

We studied the stimulus-response characteristics of cardiopulmonary baroreflex control of forearm vascular resistance (FVR) in four groups of male volunteer subjects: i) unfit, ii) physically fit, iii) before and after 10 wk of endurance training (chronic blood volume expansion), and iv) before and after acute blood volume expansion. We assessed the relationship between reflex stimulus, i.e., changes in central venous pressure and response, i.e., FVR, during unloading of cardiopulmonary mechanoreceptors with lower body negative pressure (LBNP, 0 to -20 mm Hg). The slope of the linear relationship between FVR and CVP, the index of the responsiveness of this baroreflex, was significantly diminished (> 50%) in the fit subjects compared with the unfit. The slope of the FVR-CVP relationship was inversely correlated with the subject's total blood volume, suggesting that blood volume expansion was related to the attenuated CP baroreflex. In the exercise training study, maximal oxygen consumption and blood volume increased following 10 wk of endurance training (N = 14) but were unchanged in the time control group (N = 7). The slope of the FVR-CVP relationship was significantly reduced (32%) following 10 wk of training but was unchanged in the time control group. The reduction in slope of the FVR-CVP relationship was inversely related to the increase in blood volume associated with exercise training. Acute blood volume expansion 8 ml.kg-1 body weight with 5% human serum albumin solution) significantly reduced the slope of the FVR-CVP relationship. These data support the hypothesis that the attenuated forearm vascular reflex in physically fit individuals is related to a training-induced hypervolemia.(ABSTRACT TRUNCATED AT 250 WORDS).

Review↗
NASA NTRS1988

Core temperature is regulated, although at a lower temperature, in rats exposed to hypergravic fields

1. In rats acclimated to 23 degrees C (RT rats) or 5 degrees C (CA rats), core temperature (Tc), tail temperature (Tt) and oxygen consumption (VO2) were measured during exposure to a hypergravic field. 2. Rats were exposed for 5.5 h to a 3 g field while ambient temperature (Ta) was varied. For the first 2 h, Ta was 25 degrees C; then Ta was raised to 34 degrees C for 1.5 h. During this period of warm exposure, Tc increased 4 degrees C in both RT and CA rats. Finally, Ta was returned to 25 degrees C for 2 h, and Tc decreased toward the levels measured prior to warm exposure. 3. In a second experiment at 3 g, RT and CA rats were exposed to cold (12 degrees C) after two hours at 25 degrees C. During the one hour cold exposure, Tc fell 1.5 degrees C in RT and 0.5 degree C in CA rats. After cold exposure, when ambient temperature was again 25 degrees C, Tc of RT and CA rats returned toward the levels measured prior to the thermal disturbance. 4. Rats appear to regulate their temperature, albeit at a lower level, in a 3 g field.

NASA Discipline Number 40-30↗
NASA NTRS1993

Influence of simulated microgravity on the VO2 max of nontrained and trained rats

Head-down suspension (HDS) of rats has evolved as a useful model for the simulation of a microgravity environment. Previous HDS experiments with rats have shown an impaired capacity to perform aerobic exercise as demonstrated by reductions in maximum oxygen consumption (VO2 max), treadmill run time (RT), and mechanical efficiency (ME) of treadmill running at submaximal conditions. To determine whether endurance training (TR) before HDS would modify exercise performance, male Sprague-Dawley rats were assigned to nontrained (NT) or TR groups for 6 wk and exposed to HDS or cage control (CC) conditions for 29 days. The rats were tested for VO2 max, RT, and ME before treatment and on days 7, 14, 21, and 28. In addition, water and electrolyte excretion was measured on days 1 and 21 of the experimental period. Before HDS, the TR rats had significantly higher measures of VO2 max (15%) and RT (22%) than the NT rats. On day 28, HDS was associated with significant reductions in absolute VO2 max (ml/min) in TR (-30%) and NT (-14%) rats. Relative VO2 max (ml.min-1.kg-1) was significantly reduced in TR (-15%) but not NT rats. Similar reductions in RT occurred in TR (-37%) and NT (-35%) rats by day 28. ME was reduced 22% in both TR and NT rats after 28 days of suspension. HDS elicited diuresis, natriuresis, and kaliuresis in TR rats after 21 days but not after 24 h. In contrast, HDS-NT rats exhibited no diuretic, natriuretic, or kaliuretic responses.(ABSTRACT TRUNCATED AT 250 WORDS).

Non-NASA Center↗
NASA NTRS1992

Influences of chemical sympathectomy, demedullation, and hindlimb suspension on the VO2max of rats

Results from previous studies have shown that the reduction in maximal oxygen consumption (VO2max) with simulated microgravity is attenuated in chemically sympathectomized rats. To determine the contributions of the catecholamines from the adrenal medulla in this process, investigations were conducted with 65 saline injected (SAL) and chemically sympathectomized (SX) female rats that were either surgically demedullated (DM), or intact (IN). Microgravity conditions were simulated by head-down suspension (HDS) while controls were assigned to individual cages (CC). The experimental period was 14 d. The rats were tested for VO2max, treadmill run time (RT), and submaximal mechanical efficiency (ME) prior to suspension and on days 7 and 14. Saline injected rats that had intact adrenal medullas (SAL-IN) exhibited significantly reduced measures of VO2max after 7 and 14 d by 15% and 21%, respectively. No significant reduction in VO2max was observed with HDS in the SX-IN animals. Sympathectomized rats that were demedullated (SX-DM) also exhibited a significant reduction in VO2max (12%). In addition, HDS was associated with a marked and significant reduction in RT in all groups. ME for submaximal exercise was significantly reduced after HDS in SAL-IN rats but not in the SX-IN rats. SX-DM rats experienced significant reductions in ME similar in magnitude to the SAL-IN rats. These results confirm that chemical sympathectomy attenuates the expected decrease in VO2max with HDS and suggests that circulating epinephrine contributes to this response.

Non-NASA Center↗
NASA NTRS1996

Relation of systemic and local muscle exercise capacity to skeletal muscle characteristics in men with congestive heart failure

OBJECTIVES. The present study was undertaken to further characterize changes in skeletal muscle morphology and histochemistry in congestive heart failure and to determine the relation of these changes to abnormalities of systemic and local muscle exercise capacity. BACKGROUND. Abnormalities of skeletal muscle appear to play a role in the limitation of exercise capacity in congestive heart failure, but information on the changes in muscle morphology and biochemistry and their relation to alterations in muscle function is limited. METHODS. Eighteen men with predominantly mild to moderate congestive heart failure (mean +/- SEM New York Heart Association functional class 2.6 +/- 0.2, ejection fraction 24 +/- 2%) and eight age- and gender-matched sedentary control subjects underwent measurements of peak systemic oxygen consumption (VO2) during cycle ergometry, resistance to fatigue of the quadriceps femoris muscle group and biopsy of the vastus lateralis muscle. RESULTS. Peak VO2 and resistance to fatigue were lower in the patients with heart failure than in control subjects (15.7 +/- 1.2 vs. 25.1 +/- 1.5 ml/min-kg and 63 +/- 2% vs. 85 +/- 3%, respectively, both p < 0.001). Patients had a lower proportion of slow twitch, type I fibers than did control subjects (36 +/- 3% vs. 46 +/- 5%, p = 0.048) and a higher proportion of fast twitch, type IIab fibers (18 +/- 3% vs. 7 +/- 2%, p = 0.004). Fiber cross-sectional area was smaller, and single-fiber succinate dehydrogenase activity, a mitochondrial oxidative marker, was lower in patients (both p < or = 0.034). Likewise, the ratio of average fast twitch to slow twitch fiber cross-sectional area was lower in patients (0.780 +/- 0.06 vs. 1.05 +/- 0.08, p = 0.019). Peak VO2 was strongly related to integrated succinate dehydrogenase activity in patients (r = 0.896, p = 0.001). Peak VO2, resistance to fatigue and strength also correlated significantly with several measures of fiber size, especially of fast twitch fibers, in patients. None of the skeletal muscle characteristics examined correlated with exercise capacity in control subjects. CONCLUSIONS. These results indicate that congestive heart failure is associated with changes in the characteristics of skeletal muscle and local as well as systemic exercise performance. There are fewer slow twitch fibers, smaller fast twitch fibers and lower succinate dehydrogenase activity. The latter finding suggests that mitochondrial content of muscle is reduced in heart failure and that impaired aerobic-oxidative capacity may play a role in the limitation of systemic exercise capacity.

Non-NASA Center↗
DOE OSTI2021

Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down‐regulating PCK2

We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens ) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA‐seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked‐down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin‐treated U251/U87 cells. Oridonin treatment led to PCK2 down‐regulation. Additionally, PCK2 was up‐regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti‐tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.

Lin, Jianhu↗
DOE OSTI2022

Metabolic responses to increased temperatures in three semi-aquatic turtle species from the southeastern United States

Physiological maintenance of ectotherms is largely dependent on temperature. Abrupt changes in environmental conditions can cause shifts in energy budgets, with higher temperatures requiring more energy be devoted to maintenance functions, making less energy available for other activities. As a group, freshwater turtles are of conservation concern; thus, it is important to understand their physiological responses to temperature shifts, particularly given current climate change predictions. Here, we quantified metabolic rates (MR) for three species of semi-aquatic turtles that vary in their degree of terrestriality and propensity to aestivate: chicken turtles (Deirochelys reticularia), eastern mud turtles (Kinosternon subrubrum), and eastern musk turtles (Sternotherus odoratus). Metabolic trials were performed using a flow-through respirometer at three environmentally-relevant temperatures: 25°C, 30°C, and 35°C. As expected, MRs of turtles were significantly and positively associated with increases in mass and temperature. Pairwise comparisons revealed that D. reticularia exhibited significantly higher oxygen consumption rates (VO 2 ) relative to K. subrubrum, which had significantly higher VO 2 than S. odoratus. The combination of higher metabolic rates, the tendency to terrestrially aestivate, and declining quantity of high quality thermal habitats may place some semi-aquatic turtles at a disadvantage when considering future climate scenarios. Our findings, when combined with knowledge of other ecological traits, may be a useful tool for predicting relative sensitivities of turtle species to predicted climate change, particularly those species inhabiting seasonal wetlands.

Sternotherus odoratus↗
DOE OSTI2021

PGC1α regulates mitochondrial oxidative phosphorylation involved in cisplatin resistance in ovarian cancer cells via nucleo-mitochondrial transcriptional feedback

Mitochondria play an important role in effective cell energy production and cell survival under stress conditions, such as treatment with chemotherapeutic drugs. Mitochondrial biogenesis is increased in ovarian cancer tissues, which is accompanied by alteration of mitochondrial energy metabolism, structure, and dynamics. These factors are involved in tumorigenesis and apoptosis resistance, highlighting the role of mitochondria in resisting cisplatin toxicity. Cisplatin-resistant ovarian cancer cells are dependent on mitochondrial OXPHOS for energy supply, and intracellular PGC1α-mediated mitochondrial biogenesis levels are increased in this cell line, indicating the important role of mitochondrial oxidative phosphorylation in cisplatin resistance. As PGC1α is a key molecule for integrating and coordinating nuclear DNA and mitochondrial DNA transcriptional machinery, an investigation into the regulatory mechanism PGC1α in mitochondrial energy metabolism via transcription may provide new clues for solving chemotherapy resistance. In the present study, it was demonstrated that inhibiting the expression of PGC1α decreased nuclear and mitochondrial DNA transcription factor expression, leading to increased lactic acid production and decreased cellular oxygen consumption and mitochondrial oxidative phosphorylation. Furthermore, mitochondrial stress-induced ROS production, as a feedback signal from mitochondria to the cell nucleus, increased PGC1α expression in SKOV3/DDP cells, which was involved in mitochondrial oxidative phosphorylation regulation. Collectively, the present study provides evidence that PGC1α-mediated nuclear and mitochondrial transcription feedback regulates energy metabolism and is involved in ovarian cancer cells escaping apoptosis during cisplatin treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

EGLP-1 lowers body weight better than exendin-4 by reducing food intake and increasing basal energy expenditure in diet-induced obese mice

It is well known that GLP-1 activates GLP-1R to reduce body weight by inhibiting eating. GLP-1 is cleaved by the neutral endopeptidase (NEP) 24.11 into a pentapeptide GLP-1 (32–36) amide, which increases basal energy expenditure and inhibits weight gain in obese mice. It is well known that GLP-1 analogs can reduce weight by suppressing eating. However, there are few reports of reducing weight through the dual effects of inhibiting eating and increasing basic energy. Here, we report the peptide EGLP-1, a GLP-1 analogue, which can reduce food intake and increase basal energy expenditure. In C2C12 myotubes, EGLP-1 can increase both phosphorylation of acetyl CoA carboxylase (ACC) and the ratio between phosphorylation of ACC and the total expression of ACC (pACC/ACC). In diet-induced obese mice, EGLP-1 is more effective than exendin-4 in reducing body weight, reducing fat mass and improving hepatic steatosis. At the same time, EGLP-1 can improve hyperglycemia, reduce food intake, and improve insulin resistance, just like exendin-4. In addition, EGLP-1, not exendin-4, can improve physiological parameters associated with lipid metabolism and increase oxygen consumption by increasing uncoupling proteins 3 (UCP3) expression and pACC/ACC ratio in skeletal muscle. Taken together, this data showed that EGLP-1 is able to reduce body weight by reducing food intake and increasing basal energy expenditure, suggesting it may be more effective in treating diabetic and non-diabetic overweight or obese people than pure GLP-1R agonist exendin-4.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Hyperglycemia alters mitochondrial respiration efficiency and mitophagy in human podocytes

Highlights: • Impairment of mitochondrial dynamics underlies the pathogenesis of type 2 diabetes. • Mitochondrial respiration is altered in glomeruli isolated from diabetic STZ-rats. • High glucose induces mitochondrial fission and fragmentation in human podocytes. • Mitochondrial fusion, biogenesis and mitophagy are reduced in HG-treated podocytes. • HG can injure the kidney by alteration of podocytes and glomerular bioenergetics. Podocytes constitute the outer layer of the renal glomerular filtration barrier. Their energy requirements strongly depend on efficient oxidative respiration, which is tightly connected with mitochondrial dynamics. We hypothesized that hyperglycemia modulates energy metabolism in glomeruli and podocytes and contributes to the development of diabetic kidney disease. We found that oxygen consumption rates were severely reduced in glomeruli from diabetic rats and in human podocytes that were cultured in high glucose concentration (30 mM; HG). In these models, all of the mitochondrial respiratory parameters, including basal and maximal respiration, ATP production, and spare respiratory capacity, were significantly decreased. Podocytes that were treated with HG showed a fragmented mitochondrial network, together with a decrease in expression of the mitochondrial fusion markers MFN1, MFN2, and OPA1, and an increase in the activity of the fission marker DRP1. We showed that markers of mitochondrial biogenesis, such as PGC-1α and TFAM, decreased in HG-treated podocytes. Moreover, PINK1/parkin-dependent mitophagy was inhibited in these cells. These results provide evidence that hyperglycemia impairs mitochondrial dynamics and turnover, which may underlie the remarkable deterioration of mitochondrial respiration parameters in glomeruli and podocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

EPS8 supports pancreatic cancer growth by inhibiting BMI1 mediated proteasomal degradation of ALDH7A1

Aldehyde dehydrogenase 7 family member A1 (ALDH7A1) is an enzyme catalyzing lipid peroxidation of fatty aldehydes. It plays a critical role in sustaining high oxygen consumption rate (OCR) and ATP production in pancreatic ductal adenocarcinoma (PADC). However, why PADC cells maintain a relatively high level of ALDH7A1 concentration is still not well understood. In the current study, we explored the interplay between epidermal growth factor receptor kinase substrate 8 (EPS8) and ALDH7A1 in PADC cells. PADC cell lines MIA PaCa-2 and AsPANC-1 were used for in vitro and in vivo studies. The co-IP assay showed mutual interactions between Flag-EPS8 and Myc-ALDH7A1 in both MIA PaCa-2 and AsPANC-1 cells. EPS8 knockdown resulted in decreased ALDH7A1 protein levels and increased poly-ubiquitination. An interaction was observed between ALDH7A1 and BMI1 but not between BMI1 and EPS8. BMI1 knockdown reduced ALDH7A1 poly-ubiquitination and degradation caused by EPS8 knockdown. Dual EPS8 and ALDH7A1 knockdown had a synergistic effect on suppressing PADC cell proliferation in vitro and in vivo. In conclusion, this study revealed that EPS8 supports PADC growth by interacting with ALDH7A1 and inhibiting BMI1 mediated proteasomal degradation of ALDH7A1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Getting to the Root of Plant–Mediated Methane Emissions and Oxidation in a Thermokarst Bog

Vascular plants are important in the wetland methane cycle, but their effect on production, oxidation, and transport has high uncertainty, limiting our ability to predict emissions. In a permafrost–thaw bog in Interior Alaska, we used plant manipulation treatments, field–deployed planar optical oxygen sensors, direct measurements of methane oxidation, and microbial DNA analyses to disentangle mechanisms by which vascular vegetation affect methane emissions. Vegetation operated on top of baseline methane emissions, which varied with proximity to the thawing permafrost margin. Emissions from vegetated plots increased over the season, resulting in cumulative seasonal methane emissions that were 4.1–5.2 g m –2 season –1 greater than unvegetated plots. Mass balance calculations signify these greater emissions were due to increased methane production (3.0–3.5 g m –2 season –1 ) and decreased methane oxidation (1.1–1.6 g m –2 season –1 ). Minimal oxidation occurred along the plant–transport pathway, and oxidation was suppressed outside the plant pathway. Our data indicate suppression of methane oxidation was stimulated by root exudates fueling competition among microbes for electron acceptors. This contention is supported by the fact that methane oxidation and relative abundance of methanotrophs decreased over the season in the presence of vegetation, but methane oxidation remained steady in unvegetated treatments; oxygen was not detected around plant roots but was detected around silicone tubes mimicking aerenchyma; and oxygen injection experiments suggested that oxygen consumption was faster in the presence of vascular vegetation. In conclusion, root exudates are known to fuel methane production, and our work provides evidence they also decrease methane oxidation.

58 GEOSCIENCES↗