bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of feelings of energy differ from predictors of fatigue among graduate health sciences students
Authors: Boolani Ali , O'Connor Patrick , Reed Jeri , Ma Sai , Mondal Sumona
Published: June 2021

Background

Until recently many researchers have examined energy and fatigue as opposite ends of a bipolar spectrum rather than two separate unipolar moods. Studies have also focused on a single variable to study these mood states rather than examining multiple variables simultaneously. Therefore, the purpose of this study was to identify factors predicting feelings of energy and fatigue while simultaneously examining multiple domains related to these mood states in graduate health sciences students.

Methods

Seventy‐seven subjects were recruited from a Physician Assistant, Physical Therapy and Occupational Therapy program at a small school in Northern New York. Subjects completed a series of surveys to measure mood, diet, mental work load intensity on school days and non‐school days, and physical activity. Subjects also completed the Trail‐making Test Part B task on an iPad and their Resting Metabolic Rate (RMR) and muscle oxygen consumption mVO2 was measured. A backwards linear regression was used to determine the relationship between energy, fatigue and multiple variables.

Results

The predictor variables accounted for 46.1% and 22.7% of the variance in fatigue and energy, respectively. More fatigue was associated with worse sleep quality, more time spent sitting and higher perceived intensity of mental workload on non‐school days. More energy was associated with better sleep quality, higher muscle oxygen saturation, lower RMR, and faster psychomotor performance.

Conclusion

The results of this study indicate that energy and fatigue are separate constructs that are predicted with different accuracy by different variables. Our results indicate that small lifestyle changes may be necessary to improve feelings of fatigue but comprehensive interventions may be necessary to improve feelings of energy. This study provides new insight into a multi‐domain approach to predicting energy and fatigue.

Support or Funding Information

There was no funding for this study

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exercise training ameliorates coronary endothelial dysfunction in atherosclerosis through endoplasmic reticulum stress and uncoupling protein‐2
Authors: Hong Junyoung , Park Eunkyung , Lee Jonghae , Park Yoonjung
Published: June 2021

Introduction

Prolonged endoplasmic reticulum (ER) stress, that has been known as an interrupted of ER homeostasis causing apoptosis and inflammation, is closely associated with cardiovascular diseases including atherosclerosis. Uncoupling protein (UCP)‐2 regulates mitochondrial reactive oxygen species (ROS) and its impairment may be associated with atherosclerosis. However, the role of ER stress and UCP‐2 in coronary endothelial dysfunction in atherosclerosis is unclear and no study has been conducted to determine the effect of exercise on ER stress and UCP‐2‐associated coronary arterioles dysfunction in atherosclerosis.

Methods

Wild type (WT), WT with exercise training, running on the treadmill for 12 weeks (WT‐EX), apolipoprotein E knockout (ApoE KO) and ApoE KO with exercise training (ApoE KO‐EX) mice were used for the study. To test coronary arterioles function, endothelium‐dependent (acetylcholine, ACh) vasodilation and endothelium‐independent nitroprusside (SNP) vasodilation of isolated and pressurized coronary arterioles were measured by a concentration‐dependent manner. The vessels were incubated with endothelial nitric oxide synthase (eNOS) inhibitor, NG‐nitro‐L‐arginine methyl ester (L‐NAME), ER stress inducer, tunicamycin, and uncoupling protein‐2 (UCP‐2) inhibitor, Genepin were incubated and ACh‐induced dilation were measured to investigate the underlying mechanisms.

Results

ACh‐induced vasodilation was attenuated in ApoE KO compared to WT, but exercise training ameliorated the ACh‐induced vasodilatation in ApoE KO‐EX while endotheliumin‐dependent SNP‐induced vasodilation was not different among the groups. ACh‐induced vasodilation in the presence of L‐NAME, tunicamycin and Genepin were reduced in WT, WT‐EX and ApoE KO‐EX, but not in ApoE KO.

Conclusion

Our findings suggest that exercise alleviates endothelial dysfunction in atherosclerotic coronary arterioles through the NOS, UCP‐2, and ER stress signaling pathways.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Systolic Pressure Post‐Maximal Exercise is Associated with Arterial Stiffness and Baroreflex Sensitivity
Authors: Allie Kyleigh , Kilpatrick Julianna , Salvador Paolo , Rivas Eric
Published: June 2021

Background

Arterial stiffness is associated with cardiac dysfunction and coronary artery disease. The changes of stiffness post‐exercise is dependent on exercise intensity. Low intensity decreases stiffness while supramaximal exercise increases stiffness. The reason for the increase in stiffening occurring post‐maximal exercise is not well understood and may be due to central and peripheral stiffening or baroreflex resetting from maximal exercise.

Purpose

This project tested the hypothesis that the acute increase in blood pressure post‐maximal aerobic exercise is due to central and peripheral arterial stiffness and changes in baroreflex sensitivity (indexed as Δ heart rate /Δ blood pressure).

Methods

Eight healthy active (7057±2910 steps/day) subjects (6M/2F, 25±6y, 74±17kg) completed a treadmill maximal aerobic exercise test (56.6±12.4mL·kg·min) and a time control standing condition in random order separated by at least 7 days. Heart rate (HR), peripheral blood pressure (SYS, DIA, MAP) stiffness (augmentation index; AIX, pulse wave velocity; PWV) and total vascular conductance (TVC), and central blood pressures (cSYS, cDIA) were measured at 30, 60, 90‐ and 120‐minutes post‐exercise in supine position and baroreflex sensitivity was examined at post‐30 minutes. A 2‐way repeated measures analysis of variance was used to examine interaction and main effects for condition x time. Pearson correlations determined relationships between blood pressures and stiffness measures, exercise capacity and physical activity.

Results

The change (Δ) after maximal exercise compared to time control rest for HR (Δ13±15bpm), SYS (Δ4±9mmHg), MAP (Δ5±6mmHg), cSYS (Δ4±8mmHg) and PWV (Δ0.19±0.33cm/s) was greater from 30–120 min post‐maximal exercise (condition main effect, P≤0.03). Maximal aerobic exercise did not affect DIA, AIX, or TVC. Cardiac baroreflex sensitivity was increased to a greater extent after exercise (time control: 0.2±0.4 vs maximal exercise: 4.0±5.0 bpm/mmHg; P=0.02) and the ΔcSYS was strongly associated with the Δ arterial stiffness (PWV) accounting for 76% of the variance (P=0.0001).

Conclusion

These data indicate that maximal aerobic exercise increases systemic and central systolic blood pressure that is associated with an increased stiffening that may reflect the resetting of cardiac baroreflex sensitivity acutely after maximal aerobic exercise. Further understanding of these mechanisms underlying changes in PWV following maximal exercise may be physiologically relevant to cardiac loading and examining an appropriate baroreflex response that could be impaired in disease states that requires further study.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of dietary nitrate supplementation on the speed/duration relationship in mice with sickle cell anemia
Authors: Ferguson Scott Kohman , Stenmark Kurt R , Buehler Paul , Irwin David C.
Published: June 2021

Sickle cell disease (SCD) compromises nitric oxide (NO) bioavailability and results in a plethora of cardiopulmonary and skeletal muscle complications causing severe exercise intolerance. It is now widely recognized that dietary nitrate can be reduced to nitrite and, subsequently, NO and impact hemodynamic and metabolic control during exercise. Therefore, the purpose of this investigation was to measure the impact of nitrate supplementation on exercise capacity as measured by the running speed/ exercise duration relationship (critical speed, CS) and the anaerobic work capacity (W′, the finite work capacity available above CS) in mice with SCD. We tested the hypothesis that dietary nitrate supplementation via beetroot juice (BR) would attenuate the exercise intolerance observed in mice with SCD. Ten wild‐type (WT) and 18 Berkley sickle‐cell mice (BERK) received either water (WT: n=10, BERK: n=10) or nitrate‐rich BR (BERK+BR: n=8, nitrate dose 1 mmol/kg/day) for five days). Following the supplementation period, all mice performed 4 constant‐speed treadmill tests that resulted in fatigue within 1.5 to 20 min. Time to fatigue vs. treadmill speed were fit to a hyperbolic model to determine CS. Speed and time to exhaustion for WT, BERK, and BERK+BR conformed to a hyperbolic relationship (WT: r2 = 0.93 ± 0.02, BERK: r2 = 0.97 ± 0.01, BERK+BR: r2= 0.97 ± 0.03, p>0.05). CS was significantly lower in BERK when compared to WT and BERK+BR with no significant difference between WT and BERK+BR (WT: 33.1 ± 1.5, BERK: 24.7 ± 0.7, BERK+BR: 31.9 ± 1.4 m/min, p<0.05). Additionally, the W′ was significantly higher in BERK relative to WT and BERK+BR (WT: 1456.2 ± 237.2, BERK: 2639.2 ± 106.8, BERK+BR: 1134.7 ± 156.7, P<0.05). To summarize, exercise tolerance, as measured via CS, was significantly lower in BERK mice relative to WT. However, BERK mice that had received a 5‐day dietary nitrate intervention exhibited no difference in exercise tolerance when compared to WT. In addition, the W′ was significantly higher in BERK mice relative to WT, but this difference was not observed in BERK+BR. The CS threshold is a well‐described fundamental feature of exercise energetics that represents the highest sustainable rate of aerobic metabolism and remains valid across species. Considering the lower CS in BERK mice and the ability of BR to restore CS in BERK mice, these results provide compelling support for the use of a dietary nitrate intervention to improve functionality in the SCD patient population.

Support or Funding Information

Funded by NIH (R01HL125642) to DCI and Colorado Nutrition and Obesity Research Center (P30DK048520) award to SKF.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CuZnSOD expressed specifically in neurons rescues mitochondrial function and calcium handling in muscles of Sod1KO mice
Authors: Su Yu , Macpherson Peter C.D. , Claflin Dennis R. , Van Remmen Holly , Brooks Susan V.
Published: June 2021

Background

Aging is accompanied by loss of muscle mass and force. The mechanism of the loss is not fully understood, but oxidative stress and mitochondrial dysfunction have been implicated as potential contributors. Mice deficient in CuZnSOD (Sod1−/− mice) show decreased ATP production and increased generation of reactive oxygen species by muscle mitochondria as well as muscle atrophy and weakness early in life that is reminiscent of that observed in old age in wild type (WT) mice. Thus, Sod1−/− mice represent a model of accelerated neuromuscular aging. Surprisingly, SynTgSod1−/− mice, which have Sod1 expression restored specifically in neurons, show none of the neuromuscular deficits observed in Sod1−/− mice. To investigate how neuron‐specific Sod1 expression rescues muscle mass and force in Sod1−/− mice, we examined contractile properties and mitochondrial function in muscles of SynTgSod1−/− mice.

Method

Lumbrical muscles were removed from 7–9 months old wild‐type, Sod1−/−, and SynTgSod1−/− mice, attached to a force transducer, and placed in an experimental chamber for the measurement of muscle contractile parameters and NADH fluorescence was recorded as a measure of mitochondrial redox status. Because mitochondrial function is regulated by calcium, we also examined intracellular calcium transients (ICT) using the fluorescent dye Mag‐fura2. Immunofluorescence techniques were used to examine neuromuscular junction (NMJ) structure and fiber type composition.

Result

Compared with WT muscles, mitochondria of muscles of Sod1−/− mice were in a more reduced state at rest and became transiently more oxidized following a 5s maximum isometric contraction. Consistent with the idea that recovery of NADH may be driven by calcium activation of the TCA cycle, the peak of the ICT was reduced and the width prolonged in muscles of Sod1−/− mice. For all measures, muscles of SynTgSod1−/− and WT mice were not different. A shift in muscle fiber type composition observed in Sod1−/− mice was also restored in SynTgSod1−/− mice. Moreover, NMJ denervation and fragmentation was rescued in SynTg Sod1−/− mice.

Conclusion

Our finding of improved mitochondrial function in muscles of SynTgSod1−/− compared with Sod1−/− mice is consistent with the hypothesis that the mitochondrial dysfunction is an important contributor to the development of atrophy and weakness in Sod1−/− mice. Since SynTgSod1−/− mice are still lacking CuZnSOD in muscle, we conclude that appropriate neuronal function and intact innervation are key to maintaining muscle mitochondrial function and overall muscle size and strength.

Support or Funding Information

Supported by NIH Grant AG051442 and the Second Xiangya Hospital of Central South University, China

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
δ‐Opioid agonist, [D‐Pen2,5]enkephalin (DPDPE) attenuates the exercise pressor reflex in both freely perfused and ligated rats
Authors: Kim Joyce S , Kaufman Marc P
Published: June 2021

A reflex, which is elicited by mechanical and metabolic stimuli arising in contracting muscles, is responsible in part for the increases in cardiac output, heart rate, and arterial pressure evoked by exercise. In patients with peripheral artery disease, this reflex is exaggerated and may contribute to their increased risk of adverse cardiovascular events. The afferent arm of this reflex, which is called the exercise pressor reflex (EPR), is comprised of group III and IV afferents. Both μ and δ opioid receptors are expressed on the spinal endings of these afferents which terminate in the dorsal horn of the spinal cord. Evidence suggests that δ‐opioid receptors (DOR) are expressed predominately on the spinal endings of thinly myelinated Aδ fibers (group III), whereas μ‐opioid receptors (MOR) are expressed predominately on the spinal endings of C‐fibers (group IV). Using stimuli that activated group III afferents, namely static contraction, tendon stretch, and lactic acid, we tested the hypothesis that activation of pre and postsynaptic DOR in the dorsal horn attenuated the pressor reflexes in both rats with freely perfused hindlimb muscles and in rats with hindlimb muscles whose arterial supply had been ligated for 72 hours. We activated DOR by intrathecal injection (10μg in 10μl) of the selective δ‐opioid agonist, [DPen2,5] enkephalin (DPDPE).

We found that in freely perfused rats, DPDPE significantly attenuated the EPR evoked by static contraction ( n=7; P <0.005) and the muscle mechanoreflex, the latter of which was evoked by stretching the calcaneal tendon (n=9; P <0.05). Likewise, DPDPE attenuated the pressor response to injection of lactic acid into the arterial supply of the hindlimb (n=7; P <0.05). in contrast, DPDPE did no attenuate the pressor response to arterial injection of capsaicin (n=7; P>0.5), which is a more selective stimulus to group IV afferents than it is to group III afferents. In ligated rats, DPDPE attenuated the EPR, the muscle mechanoreflex (both n=6; P<0.05) as well as the pressor response to arterial injection of lactic acid (n=6; P< 0.05). In ligated rats, however, DPDPE did not attenuate the pressor response to capsaicin (n=8; P>0.05). Intrathecal injection of saline (10μl), the vehicle for DPDPE, did not affect the EPR, the muscle mechanoreflex or the pressor responses to lactic acid or capsaicin in either FP or ligated rats. We conclude that activation of δ‐opioid receptors in the dorsal horn attenuates reflexes evoked by group III muscle afferents in both freely perfused and ligated rats.

Support or Funding Information

This work was funded by National Institutes of Health grants R01 AR059397 and P01 HL134609. The NIH is thanked for their support of this work.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endogenous Acetylcholine Limits α1‐Adrenergic Vasoconstriction During Exercise in Humans
Authors: Terwoord Janée D. , Hearon Christopher M. , Richards Jennifer C. , Luckasen Gary J. , Dinenno Frank A.
Published: June 2021

Sympathetic vasoconstriction is markedly attenuated within the vasculature of contracting compared to quiescent skeletal muscle (“functional sympatholysis”), yet the mechanisms that modulate post‐junctional α‐adrenergic signaling in active muscle remain poorly understood. In rodents, application of the endothelium‐dependent agonist acetylcholine (ACh) blunts sympathetic vasoconstriction in skeletal muscle resistance vessels, and we have recently demonstrated that intra‐arterial administration of ACh enhances functional sympatholysis in humans. Thus, we sought to determine whether endogenous ACh is involved in this integrative control of vascular tone during exercise. In 16 healthy volunteers (8 F, 8 M; 26 ± 1 yrs), we assessed the vasoconstrictor response to intra‐arterial phenylephrine (PE; α1 agonist) at rest and during rhythmic handgrip exercise under control conditions and during local inhibition of muscarinic ACh receptors via intra‐arterial atropine. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) at rest and during 4 min of dynamic handgrip contractions at two exercise intensities (15 and 25% of maximal voluntary contraction, MVC). Adenosine was infused during the resting trials to elevate FBF to levels similar to those observed during exercise. After the vascular response to exercise or adenosine reached steady‐state, we assessed vasoconstriction during infusion of PE for 2 min. The magnitude of sympatholysis was calculated as the percent reduction in vasoconstriction during exercise compared to rest. As expected, the vasoconstrictor response (Δ FVC) to PE was attenuated during exercise at 15 (−20 ± 2%) and 25% MVC (−12 ± 2%) compared with rest (−40 ± 4%; P < 0.05), indicating functional sympatholysis. Atropine did not affect sensitivity to PE at rest (−38 ± 4%; P = 0.60). During 15% MVC exercise, atropine augmented vasoconstriction to PE in women (−25 ± 2 vs. −19 ± 2%, P < 0.05), whereas it did not affect the response in men (−22 ± 2 vs. −22 ± 3%, P = 0.88). During higher intensity exercise, atropine reduced the magnitude of functional sympatholysis by ~50% such that a greater degree of vasoconstriction occurred in response to PE in both women (−22 ± 4 vs. −11 ± 4%, P < 0.05) and men (−22 ± 2 vs. −12 ± 2%, P < 0.05) compared to control conditions. These findings demonstrate that inhibition of muscarinic receptors reduces the ability of contracting muscle to limit sympathetic vasoconstriction in an intensity‐ and sex‐dependent manner, supporting a novel, physiological role for ACh in functional sympatholysis in humans.

Support or Funding Information

Supported by HL119337 & HL142240

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High‐Intensity Interval Training and Moderate‐Intensity Continuous Training Improve Endothelial Function Similarly in Adults with Type 2 Diabetes
Authors: Hwang Chueh‐Lung , Lim Jisok , Yoo Jeung‐Ki , Kim Han‐Kyul , Hwang Moon‐Hyon , Handberg Eileen M. , Petersen John W. , Sakarya Yasemin , Holmer Brady J. , Lapierre Stephanie S. , Leey Casella Julio A. , Cusi Kenneth , Christou Demetra D.
Published: June 2021

Endothelial function is a predictor of cardiovascular disease, the leading cause of death in adults with type 2 diabetes. Aerobic exercise training may preserve or improve endothelial function; however, the optimal exercise prescription remains uncertain. Recently, there has been increasing interest in high‐intensity interval training (HIIT) vs. moderate‐intensity continuous training (MICT). These protocols are most commonly performed on the treadmill which may limit implementation in patients who have lower limb limitations or balance issues. We sought to compare the effect of non‐weight‐bearing all‐extremity HIIT vs. MICT on endothelial function in adults with type 2 diabetes. Forty‐nine sedentary men and postmenopausal women with type 2 diabetes aged 46 to 78 yrs (mean±SE: 63±1 yrs), free of cardiovascular disease, were randomized to HIIT (n=18), MICT (n=16), or non‐exercise control (CONT; n=15). HIIT (4×4‐min intervals at 90% of peak heart rate (HRpeak) interspersed by 3 min recovery bouts at 70% HRpeak) and isocaloric MICT (32 min at 70% of HRpeak) were performed on an Airdyne® all‐extremity ergometer 4 days/week under supervision. Including warm‐up and cool‐down, the total exercise duration per session was 40 min for HIIT and 47 min for MICT. Endothelial function in response to reactive hyperemia was assessed non‐invasively by brachial artery flow‐mediated dilation (FMD) via ultrasonography. Following the 8‐week intervention, FMD increased similarly in HIIT (pre‐ vs. post‐intervention: 3.17±0.62 vs. 4.03±0.71%, P=0.01) and MICT (3.54±0.63 vs. 4.39±0.61%; P=0.02 and P>0.99 for HIIT vs. MICT) while it did not change in CONT (4.02±0.46 vs. 3.74±0.51%, P=0.4). The improvement in FMD was not confounded by changes in brachial baseline diameter, hyperemic shear rate, or systolic and diastolic blood pressure (P≥0.3). In conclusion, all‐extremity HIIT and MICT similarly improve endothelial function in adults with type 2 diabetes which suggests that all‐extremity MICT is an effective alternative for those who are unable or unwilling to engage in all‐extremity HIIT.

Support or Funding Information

This work was supported by National Institute of Aging grant AG050203 to DDC.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Duration of Remote Ischemic Preconditioning on the Skin Microvascular Response to Local Heating
Authors: Uridil Audrey I , Kim Jahyun , Lang James A
Published: June 2021

Introduction

Remote ischemic preconditioning (RIPC), or intermittent periods of ischemia followed by reperfusion, improves endothelial function in conduit vessels; however, whether functional changes occur in the microvasculature is unknown. Using skin as a microvascular model, we hypothesized that the cutaneous vasodilation (VD) response to localized heating would progressively increase with duration of RIPC treatment.

Methods

Twelve young adults performed RIPC for two weeks whereas nine completed one week of RIPC. Each RIPC session included 4 repetitions of 5 minutes of arm blood flow occlusion followed by 5 minutes reperfusion. Before and after the RIPC intervention, the skin VD response to localized heating (Tloc = 42°C) was measured using laser speckle contrast imaging (LSCI). Data were normalized to cutaneous vascular conductance (CVC); LSCI flux / mean arterial pressure (MAP).

Results

Baseline CVC and MAP remained unchanged following RIPC (p > 0.05). However, the plateau in the cutaneous VD response to localized heating was augmented after one week of RIPC (Pre: 1.16 ± 0.44, Post: 1.48 ± 0.57 LDF·mmHg−1; p < 0.05) but no further improvement was observed after two weeks of RIPC (Pre: 1.50 ± 0.30, Post: 1.63 ± 0.36 LDF·mmHg−1; p < 0.05). Delta CVC values (post – pre RIPC) were not different between one week and two weeks of RIPC (p = 0.14).

Discussion

These data indicate that repeated bouts of RIPC augments cutaneous microvascular function and suggests that the adaptations with repeated RIPC may have an endothelium‐mediated component. And, longer duration of RIPC did not elicit greater functional changes.

Support or Funding Information

Iowa Space Grant Consortium (NASA STEM Training Grant) (#134819)

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Advanced Glycation End Products in Neutrophil Extracellular Trap Formation
Authors: Cooney Riley , Ahmadi Layla , Petreaca Melissa
Published: June 2021

During inflammatory responses, innate immune cells such as neutrophils are recruited to the site of infection to fight and kill foreign microbes. Neutrophils eliminate these potential pathogens in three distinct ways: phagocytosis, the generation of toxic reactive oxygen species (ROS), and the production of neutrophil extracellular traps (NETs). NETs, consisting of expelled DNA and associated proteins, bind and capture bacteria, making them easier for neutrophils to kill via ROS and antimicrobial histone functions. In cases involving microbial contamination, inflammation is beneficial and indeed necessary to prevent infection. However, in many disease contexts, inflammation persists despite an absence of pathogens, and the ROS and NETs that otherwise damage and kill pathogens instead damage and kill host tissues. This type of chronic inflammation is often present in Type II diabetics who have persistent high blood glucose levels or hyperglycemia. Hyperglycemia is correlated with neutrophil priming during NET formation and delayed wound healing, suggesting one mechanism linking hyperglycemia with chronic inflammation. However, the mechanisms underpinning hyperglycemia‐induced NET formation remain unclear. Hyperglycemic patients have increased concentrations of advanced glycation end products (AGEs), generated by sugars randomly and irreversibly attaching to the ends of proteins and lipids. AGEs then activate the receptor for advanced glycation end products (RAGE), resulting in pro‐inflammatory signaling that culminates in additional neutrophil recruitment and activation under hyperglycemic conditions. We are investigating whether the increases in NET production when cells are exposed to AGEs before treatment with NET‐inducing stimuli are mediated by RAGE, and found that inhibition of RAGE blocks the AGE‐enhanced, PMA‐induced NET formation in neutrophil‐like HL‐60 cells. Our results supports the therapeutic potential of RAGE inhibitors to reduce NET formation and thereby NET‐associated tissue inflammation and tissue damage in Type II diabetes. We are currently performing experiments to determine whether in normal human polymorphonuclear cells (PMNs), AGE‐enhanced NET production in response to lipopolysaccharide (LPS) is also mediated by RAGE to determine whether AGE‐RAGE interactions prime NET formation in a more physiological system.

Support or Funding Information

DePauw University and the Arthur Vining Davis Foundation

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glutathione Potential and Levels of Hydrogen Peroxide in Vulnerable Parkin Loss‐of‐Function Drosophila Neurons
Authors: Keoseyan Petros Peter
Published: June 2021

Parkinson's Disease is a neurodegenerative disorder brought on by the loss of cells in the substantia nigra pars compacta (SNpc).1 The mechanism of selective neurodegeneration in this region is yet to be elucidated. A small subset of PD patients inherits a disease‐causing mutation of the PRKN gene which encodes for parkin. The inheritance of homozygous PRKN mutations and subsequent expression of the dysfunctional parkin protein is thought to result in decreased mitochondrial protein turnover.2 Decreased turnover of damaged mitochondrial proteins could result in decreased mitochondrial respiration and increased reactive oxygen species (ROS) production. Indeed, parkin loss‐of‐function patient samples and models exhibit increased levels of reactive oxygen species (ROS).3

We have previously reported a selective increase in mitochondrial protein oxidation in degenerating dopaminergic neurons in parkin null Drosophila. We hypothesize that this results from increased hydrogen peroxide (H2O2) levels and/or decreased glutathione redox potential (EGSH).4

To determine relative H2O2and EGSH, we measured total volumes of mitochondrially‐targeted redox‐sensitive GFP (roGFP) when it is fused to yeast oxygen receptor peroxidase 1 (orp1) or human glutaredoxin 1 (grx1) in the protocerebral posterior lateral 1 (PPL1) dopaminergic cluster. The maximum excitation wavelength of roGFP shifts from 488 to 405 nm when oxidized. By measuring the volume ratios of roGFP0‐orp1 and roGFP0‐grx1 excited by 405 nm over those excited by 488 nm, we can determine relative levels of H2O2 and EGSH, respectively.

We demonstrated that parkin loss causes increases in H2O2 levels and (EGSH) in Drosophila dopaminergic neurons that are homologous to the mammalian SNpc. Our data suggest that increased H2O2levels contribute to mitochondrial protein oxidation and that decreased glutathione activity does not seem to be implicated. Strategies aimed at reducing H2O2 levels or increasing antioxidant activity may buffer the effects of decreased mitochondrial protein turnover caused by parkin loss of function.

Support or Funding Information

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Does the Synthetic Corticosteroid, Prednisolone, Impact the Insulin‐Like Growth‐Factor Binding Protein (igfbp) Network of Atlantic Salmon Parr?
Authors: Chang Annaliese , Kalinowski Matthew , McCormick Stephen , Kelly John , Breves Jason
Published: June 2021

The growth performance of teleost fishes is largely controlled by the growth hormone (Gh)/insulin‐like growth‐factor (Igf) system. Furthermore, Igfs interact with an expanded suite of cognate binding proteins, termed Igf binding proteins (Igfbps), produced by key metabolic tissues such as liver and muscle. Igfbps modulate the biological activities of Igfs under various physiological situations, such as when a glucocorticoid stress response has been mounted. In juvenile Atlantic salmon (Salmo salar), we have previously identified two igfbp genes, namely igfbp1b1 and igfbp1b2, that increase their expression in response to the endogenous glucocorticoid cortisol. These responses underlie, in part, the inhibition of anabolic processes known to occur in parallel with a glucocorticoid stress response. In the current study, we tested the hypothesis that the synthetic corticosteroid, prednisolone, may similarly inhibit anabolic processes by impacting the Gh/Igf/Igfbp network. We implanted Atlantic salmon parr with prednisolone (0, 2.5 and 25 μg/g body weight) or cortisol (25 μg/g) and sampled individuals after 14 days. We observed reduced growth rates (fork length) following treatment with the high dose of prednisolone (25 μg/g) and cortisol. We will report igfbp transcript levels in liver and skeletal muscle to resolve whether activities within the Igfbp network are modulated by prednisolone in juvenile Atlantic salmon.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of blocking muscarinic receptors using atropine on thyroarytenoid muscle recruitment during swallow and breathing
Authors: Mian Seema , Huff Alyssa D , Reed Mitchell D , Iceman Kimberly , Pitts Teresa
Published: June 2021

Atropine, a muscarinic acetylcholine receptor antagonist, is a commonly used drug to reduce mucous production during surgery. Because atropine blocks the parasympathetic action of acetylcholine, atropine may modulate the balance of parasympathetic and sympathetic activity. In jaw muscles, increased sympathetic drive decreases muscle contractility and reduces muscle spindle feedback. There is evidence for sympathetic innervation of laryngeal muscles, however, few studies have investigated the effects of changing sympathetic drive to laryngeal muscle recruitment during specific behaviors. As such we hypothesized that blocking parasympathetic activation would attenuate laryngeal muscle drive during swallow and breathing. To investigate, we blocked muscarinic receptors via IV infusion of atropine in a dose dependent manner (0.02, 0.07, 0.2, 0.7, 2.0, 7.0 mg/kg). Using steel wire electrodes, bipolar electromyography (EMG) recordings were made in upper airway muscles (mylohyoid, geniohyoid, thyroarytenoid and thyropharyngeus) and the costal diaphragm in Sprague Dawley rats. Swallow was induced by administering 1cc of water into the oral pharynx via syringe. Duration and amplitude of thyroarytenoid (ThAr) activity was measured during breathing and swallow for each concentration of atropine. There was a differential effect of thyroarytenoid EMG activity with a significant reduction during swallow with no change in drive during breathing. Additionally, there was no significant change in number of elicited swallows. These results suggest attenuation of parasympathetic activity on laryngeal muscles may differentially change motor recruitment during specific behaviors such as swallow and breathing.

Support or Funding Information

This work was supported by NIH grants HL 111215, HL 103415 and OT20D001983, the Craig F. Neilson Foundation Pilot Research Grant 546714, Kentucky Spinal Cord and Head Injury Research Trust, and the Commonwealth of Kentucky Challenge for Excellence.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Brain Stem Circuit Operations during Baroreceptor Modulation of the Motor Pattern for Breathing
Authors: Lindsey Bruce G. , Nuding Sarah C. , Segers Lauren S. , Morris Kendall F.
Published: June 2021

Circuit operations in the raphe‐pontomedullary network for breathing remain incompletely understood (Nuding et al. J Neurophysiol 101: 2943, 2009; Lindsey et al., Physiology, 33: 281, 2018). Current models for baroreceptor tuning of the respiratory motor pattern include parallel raphe‐ventral respiratory column (VRC) “push‐pull” circuits for regulation of respiratory phase timing and inspiratory drive (Lindsey et al. J Physiol, 512: 863, 1998; Segers et al. J Neurophysiol 113: 352, 2015). To extend prior work, we tested the hypothesis that inter‐regional loop circuits among neurons of the VRC, pons, and raphe nuclei have altered activities appropriate for roles in the tuning of respiratory drive and rhythm during changes in systemic arterial blood pressure. In 7 decerebrate vagotomized neuromuscular‐blocked cats, we used multi‐electrode arrays to record the activities of VRC (n=88), pontine (n=87), and raphe (n=188) neurons during baroreceptor‐evoked perturbations of breathing, as measured by altered peak activity in integrated efferent phrenic nerve activity and changes in respiratory phase durations. Blood pressure was transiently (30 sec.) elevated or reduced by inflations of an embolectomy catheter in the descending aorta or vena cava, respectively. Trials were separated by 1.5‐min intervals to allow the mean systemic arterial pressure to return to pre‐stimulus levels. Spike trains of 10,530 pairs of neurons were evaluated for changes in firing rate and short‐time scale correlational signatures indicative of functional connectivity. The results include evidence for: (i) baroreceptor modulation of a VRC‐pontine inspiratory off‐switch loop; (ii) a VRC inspiratory neuron chain disinhibitory microcircuit for baroreceptor tuning of the drive to breathe that operates in parallel with VRC tonic expiratory (t‐E) “hub” neurons; (iii) multiple push‐pull control pathways between baroresponsive raphe assemblies and the VRC t‐E neurons; (iv) divergent paths from the VRC to raphe circuits, including routes through the pons. Overall, the results provide additional support for parallel chain and loop operations in the brain stem network that controls breathing (Morris et al. J Neurophysiol 119:700, 2018).

Support or Funding Information

Support: NIH Grant NS19814 and Common Fund OT2OD023854.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chronic Alcohol Administration Induces Inflammasome Activation in Mouse Lungs
Authors: Yeligar Samantha , Cingolani Francesca , Li Juan , Bedi Brahmchetna , Sadikot Ruxana , Czaja Mark
Published: June 2021

Objective

Excessive alcohol misusers are 2–4 times more likely to develop respiratory infections and acute respiratory distress syndrome as compared to non‐alcoholics. Alcohol misuse enhances oxidative stress in the lung, leading to impaired lung immunity. The molecular mechanisms by which this lung immune dysfunction occurs remain poorly defined. Inflammasome activation occurs in alcoholic steatohepatitis and functions in oxidative stress and host defense. Autophagy is critical for the engulfment and degradation of intracellular pathogens and regulates inflammasome activation. Thus, we hypothesized that autophagy prevents oxidative stress and inflammasome activation in the lung induced by alcohol.

Methods

Lungs were collected from littermate Atg5F/F control or LysM‐Cre‐Atg5F/F mice with a macrophage‐specific knockout of the autophagy gene Atg5 that were fed either a control or ethanol‐containing (5% vol/vol) Lieber‐DeCarli diet for 5 weeks. Markers of oxidative stress and inflammation were measured in the lungs from these mice. mRNA levels of NADPH oxidase 4 (Nox4) and transforming growth factor beta (TGFβ) were assessed by qRT‐PCR. Protein expression of NLRP3, caspase‐1 and ASC were measured by western blotting and interleukin (IL)‐1β was quantitated by ELISA.

Results

In vivo studies demonstrated that alcohol: 1) increased the mRNA levels of Nox4 and TGFβ; 2) increased components of the inflammasome complex, namely NLRP3, ASC and caspase‐1; and 3) elevated IL‐1β expression, indicative of inflammasome activation. Knockdown of Atg5 enhanced inflammasome activation and exacerbated the oxidative stress and inflammatory effects of alcohol.

Conclusions

Macrophage autophagy likely plays a critical role in regulating lung oxidative stress and inflammasome activation during chronic alcohol ingestion. Inactivation of the autophagic pathway exacerbates the deleterious effects of alcohol. Therapeutic targeting of autophagy or inflammasome activation pathways could mitigate alcohol's detrimental effects on the lung and improve lung host immune defense.

Support or Funding Information

Research Funding Source: Department of Veterans Affairs 2I01BX001786 (RTS), and National Institute of Alcohol Abuse and Alcoholism 4R00AA021803 (SMY) and 5R01AA022601 (MJC).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Release of a contractile factor and reduced nitric oxide from isolated pulmonary resistance vessels from BalB/CJ mice cause higher reactivity to angiotensin II compared to C57BL/6J mice
Authors: Becirovic‐Agic Mediha , Hultström Michael
Published: June 2021

Pulmonary arterial hypertension (PAH) is caused by increased pulmonary vascular resistance that can develop as part of other pathologies such as pulmonary embolism and heart failure, or because of pulmonary vascular remodeling. The role of angiotensin II in pulmonary hypertension has not been extensively studied, and some conflicting results have been presented.

We have seen that Balb/CJ mice treated with angiotensin II and high salt diet (AngII+Salt) develop increased pulmonary vascular resistance and right ventricle systolic pressure already 24 hours following treatment initiation. Within the following 6 days, Balb/CJ mice develop massive edema and heart failure. C57Bl/6J mice on the other hand are resistant to this treatment. We hypothesized that pulmonary vessels in Balb/CJ mice are more reactive to angiotensin II than in C57BL/6J mice. The aim of present study was to investigate isolated pulmonary resistance vessel reactivity in Balb/CJ and C57BL/6J mice using wire myography.

The results show that pulmonary resistance vessels from Balb/CJ mice have enhanced vascular reactivity to angiotensin II, which abolished in denuded vessels. Pulmonary resistance vessels from C57BL/6J mice on the other hand show little or no response to angiotensin II. However, transfer of bath solution from Balb/CJ pulmonary vessels to C57BL/6J pulmonary vessels induces as strong contraction as in Balb/CJ mice. This indicates that angiotensin II causes increased vascular contraction in Balb/CJ mice, mainly by stimulating release of a secondary substance from the endothelium which in turn causes strong contraction. Further, acetylcholine induced relaxation is weaker in pulmonary arteries from Balb/CJ mice compared to C57BL/6J mice, while sodium nitroprusside induced relaxation does not differ between the strains indicating a difference in endothelial nitric oxide production as well.

In conclusion, pulmonary artery endothelial function is different between Balb/CJ and C57BL/6J mice, causing increased vascular reactivity to angiotensin II, by stimulating release of a substance that in turn causes contraction both in BalB/CJ mice and C57BL/6J mice. In addition, Balb/CJ show reduced relaxation after acetylcholine. These results may increase the understanding of the role of angiotensin II in pulmonary hypertension, as well as shed some light on increased susceptibility to pulmonary hypertension in patients with a reactive phenotype.

Support or Funding Information

Swedish Society of Medical Research, and the Swedish Heart‐Lung Foundation.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
NIH's Consortium on Molecular Transducers of Physical Activity (MoTrPAC)
Authors: Williams John P. , Joseph Lyndon , Consortium MoTrPAC
Published: June 2021

Physical activity is beneficial to human health and well being across the lifespan. Regular physical activity brings about numerous health benefits, however most of the current studies are correlative and the molecular mechanisms that are the basis for these beneficial effects remain obscure.

The NIH Common Fund initiated the Molecular Transducers of Physical Activity Consortium (MoTrPAC) in December 2016 by issuing 19 grants to 37 Principal Investigators from 23 institutions. The goals of MoTrPAC are to:

Aim 1: Assemble a comprehensive map of the molecular changes that occur in response to exercise and provide insights into how they are altered by age, sex, body composition and fitness level.

Aim 2: Develop a user‐friendly database to facilitate investigator‐initiated studies and catalyze the field of physical activity research whereby researchers can develop hypotheses exploring novel mechanisms by which physical activity improves or preserves health.

MoTrPAC is a large discovery project that will explore and document molecular signatures/markers of the exercise response to physical activity in humans and animals. The human studies are a multi‐center clinical trial cohort of people from 10–80 years of age. Animal studies have been conducted and tissues harvested from 6 and 18‐month old F344 rats before and at seven time points post acute exercise. Other rats underwent a training regime ranging from one to eight weeks and tissues harvested 48 hours after the last bought. Three of the animal tissues harvested are the same as those harvested from human subjects. A total of 18 tissues were harvested from rats. Multiple state of art and omics platforms including genomic, transcriptomic, epigenomic, proteomic and metabolomics will be employed to collect extensive data sets that will serve as a basis for future investigator initiated studies for the research community to advance our understanding of the molecular mechanisms of exercises effects. This presentation will describe various components of MoTrPAC consortium and provide information on its current activities.

Support or Funding Information

NIH Common Fund; Office of the NIH Director

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of the ganglioglomerular nerve in response to hypoxia in juvenile rats
Authors: Coffee Gregory A , Getsy Paulina M , Lewis Stephen J
Published: June 2021

The superior cervical ganglion (SCG) sends sympathetic input to the carotid body (CB) via the ganglioglomerular nerve (GGN) in order to modulate carotid sinus nerve (CSN) chemosensory afferent discharge via controlling vascular tone. This chemoafferent discharge is then relayed to the nucleus tractus solitarius (NTS) where the information is processed resulting in a compensatory increase in respiration. Hypoxic gas challenge stimulates the GGN. However, little is known as to the effects of ganglioglomerular nerve transection (GGNx) on carotid body chemosensory afferent response to hypoxia (HX).

Our objective was to determine the effect of unilateral GGNx on the ventilatory responses elicited by HX (10% O2, 90% N2) gas challenge (5 episodes of 5 min in duration separated by 15 min) in freely‐moving juvenile (P25) Sprague‐Dawley rats.

Male rats postnatal (P) 21 were subjected to sham or unilateral (right or left) GGNx and were allowed 4 days to recover. On the day of the experiment, P25 rats were placed in whole‐body plethysmography chambers and subjected to the hypoxic gas exposure. Ventilatory parameters included frequency of breathing, tidal volume, minute ventilation (= frequency x tidal volume), inspiratory and expiatory times, end inspiratory and expiratory pauses, peak inspiratory and expiratory flows, inspiratory and expiratory drive, EF50 (expiratory flow at 50% expired tidal volume) and rejection index (percentage of abnormal breaths).

The HX challenge elicited altered ventilatory responses in sham‐operated rats compared to unilateral GGNx. Rejection Index (%) was diminished in unilateral (left and right) GGNx rats compared to sham, in addition to Rpef in only the right GGNx rats. Peak inspiratory flow (mL/s) was increased in only left GGNx rats, while the peak expiratory flow (mL/s) rates were increased in both the right and left GGNx subjects. Minute ventilation (mL/min) exhibited ventilatory roll‐off in sham animals while no such trend was observed in left GGNx rats. Although peak inspiratory flow, inspiratory drive (mL/s), and expiratory drive (mL/s) reached similar plateaus in right GGNx, the onset of the responses was delayed when compared to their sham counterparts. End expiratory pause (msec) showed a more robust response following hypoxic challenge in right GGNx when viewed against the sham. These findings follow a similar trend to those previously demonstrated from unilateral SCG removal, but still possess characteristics that are unique to the GGN alone. This which suggests the role the SCG has in modulating the hypoxic response is through the GGN and the CB, as well as other yet unknown mechanisms.

Support or Funding Information

NIH SPARC 1OT2OD023860‐02 SJLewis

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.