bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Circulating microRNA Expression after Bed Rest: Potential Role in Cardiovascular Deconditioning
Authors: Ade Carl J
Published: June 2021

Bed rest, an analog of spaceflight microgravity, elicits changes in left ventricular loading conditions resulting in cardiac deconditioning that adversely effects functional outcomes and cardiopulmonary exercise performance. Given the significant and time‐dependent changes in cardiovascular function associated with bed rest, a continued evaluation of these adaptations are required, particularly in regards to their molecular regulators. MicroRNAs are noncoding RNA that regulate gene expression, with several plasma‐based ‘circulating’ microRNAs (c‐miRs) used as biomarkers of tissue‐specific physiologic adaptation. Quantification of cardiac‐c‐miRs may allow for manifestations of cardiovascular deconditioning to be identified and be used to predict cardiovascular related outcomes in response to bed rest. Therefore, the primary aim of this study was to test the hypotheses that cardiovascular‐c‐miRs are differentially expressed following bed rest and their changes associated with decreases in cardiac function and cardiopulmonary exercise capacity. Eleven participants completed 30‐days bed rest at an ambient CO2 of 0.05% (replicate CO2 levels on the International Space Station). Blood samples were obtained prior to and immediately following bed rest. 44‐targeted c‐miRs identified from published roles in cardiovascular structure/function were analyzed via RT‐qPCR. Resting stroke volume was evaluated via ultrasonography. Peak oxygen uptake (peakVO2) was determined using a grade exercise test. Ten cardiovascular‐c‐miRs were significantly increased following bed rest. The differentially expressed c‐miRs were grouped into clusters according to their expression profile. Cluster A included c‐miRs that have been identified as regulators of cardiac function and hypertrophy (c‐miR‐133), atrial fibrillation and mitochondrial function (c‐miR‐1), skeletal muscle atrophy (c‐miR‐1), vascular control (c‐miR‐155) and aerobic capacity (c‐miR‐133). Cluster B contained c‐miR identified as regulators of cardiac hypertrophy (c‐miR‐30, c‐miR‐15), fibrosis (c‐miR‐22, c‐miR‐18), mitochondrial function (c‐miR‐181), and aerobic capacity (c‐miR‐20a). Following bed rest stroke volume was decreased and correlated with changes in cmiR‐18a and c‐miR‐378a. PeakVO2 was decreased and correlated with changes in c‐miR‐133. In conclusion, we found that bed rest induced a distinct and specific cardiovascular‐c‐miR response, which was associated with changes in cardiac function and cardiopulmonary exercise capacity. Although future work is required, these results suggest the potential value of c‐miRs as biomarkers and their possible role as physiological mediators of cardiovascular deconditioning to bed rest.

Support or Funding Information

National Aeronautics and Space Administration (NASA) research grant awarded to C.J Ade

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Age‐Associated Differences in Central Artery Responsiveness to Sympathoexcitation: Influence of Blood Pressure
Authors: Bock Joshua M , Hughes William , Sheehy Kathryn , Asama Thomas , Horak Jeffrey , Casey Darren
Published: June 2021

Aging is associated with increased central artery stiffness, a potential consequence of greater tonic sympathetic nerve activity. However, less is known regarding age‐associated changes in central artery responsiveness to acute sympathoexcitation. Therefore, we tested the hypothesis that older adults would demonstrate greater increases in central artery stiffness (carotid‐femoral pulse wave velocity, cfPWV) and wave reflection (augmentation index, AIx) during the cold pressor test (CPT) compared to young adults. To control for the potential confound of blood pressure on our measurements we also employed lower‐body negative pressure (LBNP), a sympathoexcitatory stimuli with minimal influence on blood pressure. We hypothesized that older adults would have less reduction in AIx during LBNP compared to the young adults. Fourteen young (25±4yrs) and 15 older (68±4yrs) subjects completed three minutes of LBNP and CPT on a single study visit, separated by a 15‐minute washout period, in random order. Duplicate measures of cfPWV and AIx were taken at baseline and during the final minute of each perturbation. Baseline heart rate and mean arterial pressure (MAP) were not different between groups (p≥0.05 for both); however, young subjects had lower baseline cfPWV and AIx compared to older subjects (p<0.05 for both). In response to the CPT, heart rate, MAP, cfPWV, and AIx increased in both young and older groups (main effect of time p<0.01 for all); however, the change (Δ) in MAP (18±7 vs. 9±5mmHg), cfPWV (1.3±0.7 vs. 0.6±0.9m·sec−1), and AIx (17±9 vs. 7±4%) were greater in young compared to older subjects, respectively (p<0.05 for all). In response to LBNP, the changes (Δ) in MAP (−1±3 vs. −3±5mmHg), and cfPWV (0.5±0.3 vs. 0.5±0.7m·sec−1) were similar between age groups (main effect of time p<0.05 for all) although young subjects showed a greater reduction in AIx compared to their older counterparts (−8±7 vs. −2±6%, p<0.01). Interestingly, when MAP was used as a covariate, the group‐by‐time interaction for cfPWV and AIx during the CPT as well as AIx during LBNP were no longer significant (p=0.48, 0.11, and 0.39, respectively). Given that the age‐associated differences in cfPWV responsiveness to the CPT was mitigated with MAP as a covariate, and the increase in cfPWV was not different between groups in response to LBNP (no change in MAP), our data suggest age‐associated differences in central artery responsiveness to sympathoexcitation are greatly influenced by changes in MAP.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Are Spontaneous Low Frequency Oscillations in Arterial Pressure and Cerebral Blood Flow Associated with the Protection of Cerebral Tissue Oxygenation during Simulated Hemorrhage?
Authors: Anderson Garen K. , Rosenberg Alexander (A.J.) , Kay Victoria L. , Sprick Justin D. , Rickards Caroline A.
Published: June 2021

Introduction

Prior studies have independently demonstrated that subjects with higher tolerance to simulated hemorrhage elicited by lower body negative pressure (LBNP) exhibit maintenance of cerebral tissue oxygenation, and higher amplitude in spontaneously generated low frequency (~0.1 Hz) oscillations in arterial pressure and cerebral blood flow. We hypothesized that these two independent observations are related, wherein subjects with higher tolerance to LBNP would exhibit increased low frequency power in arterial pressure and cerebral blood flow, which may contribute to the protection of cerebral tissue oxygenation.

Methods

Healthy male (n=19, 25±1 y) and female (n=13, 28±1 y) subjects participated in a stepwise LBNP protocol to pre‐syncope. Mean arterial pressure (MAP), middle cerebral artery velocity (MCAv), cerebral tissue oxygen saturation (ScO2), and end tidal CO2 (etCO2) were measured continuously. Subjects were classified as high tolerant if they completed the −60 mmHg step of LBNP. Low frequency oscillations in MAP and MCAv were assessed in the 0.04–0.15 Hz range. Both time and frequency domain data were analyzed using a linear mixed model analysis of variance with Tukey post hoc tests. Comparisons were made at baseline across LBNP stages (−15, −30, −45, and −60 mmHg).

Results

Of the 32 subjects tested, 20 were classified as high tolerant and 12 as low tolerant. No differences were observed between high and low tolerant subjects in MAP (P=0.28), low frequency power of MAP (P=0.13), or low frequency power of MCAv (P=0.24) during LBNP. However, high tolerant subjects exhibited greater protection against reductions in ScO2 (P<0.01), MCAv (P<0.01), and etCO2 (P<0.01) compared to low tolerant subjects during LBNP.

Conclusion

Contrary to our hypothesis, low frequency oscillations in MAP and MCAv did not account for the observed protection in ScO2 for high tolerant subjects. Rather, maintenance of oxygen delivery (indexed via MCAv) appeared to account for the protection in cerebral oxygenation in this cohort of young, healthy subjects.

Support or Funding Information

Funding for this study was provided by the U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐2‐0137, and a contract with Pendar Medical LLC. The content is solely the responsibility of the authors and does not necessarily represent the official views the US Department of Defense.

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 exercise reduces tolerance to a simulated hemorrhagic challenge relative to steady state exercise in heat stressed individuals
Authors: Trotter Claire E , Pizzey Faith K , Batterson Philip M , Jacobs Robert A , Pearson James
Published: June 2021

Individuals who are exposed to an increased risk of experiencing a hemorrhagic insult, such as soldiers and firefighters, are often required to complete intermittent high intensity exercise in the presence of environmental heat stress. In normothermic conditions, increases in heart rate and reductions in vascular resistance can be greater following high intensity interval exercise relative to continuous steady state exercise. These hemodynamic alterations following high intensity interval exercise may reduce the capacity to withstand a hemorrhagic insult. We investigated whether high intensity interval exercise reduces tolerance to a simulated hemorrhagic challenge (lower body negative pressure; LBNP) relative to steady state exercise in heat stressed individuals. Eight healthy participants (Age: 27 ± 5 years; Ht: 179 ± 9 cm; Wt: 78.9 ± 18.7 kg) completed two trials (Steady state and Interval). Participants performed cycling exercise either by alternating between 10 and 88% (Interval) or continuously at 38% (Steady state) of the predetermined maximal aerobic power output whilst wearing a warm water perfused suit until core temperatures increased by 1.40 ± 0.21°C. Participants then underwent progressive LBNP (−20mmHg, −30mmHg, etc.) to pre syncope. LBNP tolerance was quantified as cumulative stress index (CSI; mmHg*min). Following exercise and prior to LBNP, mean skin temperatures were similarly elevated from baseline in both trials (from: 32.35 ± 0.42 to 37.95 ± 0.59°C, P < 0.05). Mean arterial pressure was not different between trials prior to LBNP (Interval: 79 ± 6 vs. Steady state: 77 ± 7 mmHg; P = 0.57) and were similarly reduced in both trials at pre syncope (to 63 ± 6 and 62 ± 6 mmHg respectively, both P < 0.05). CSI was lower in the interval trial relative to the steady state trial (280 ± 204 vs. 518 ± 285 mmHg*min, respectively; P = 0.024). In heat stressed individuals, tolerance to a simulated hemorrhagic challenge was reduced following high intensity interval exercise relative to steady state exercise. These findings have implications for individuals who exercise at intermittent high intensities in hot environments and are at increased risk of experiencing a hemorrhagic injury (e.g. soldiers, firefighters and miners).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Childhood Adversity Impairs the Autonomic Response to Acute Stress
Authors: Looney Jacob , Tucker Matthew A. , Jeong Jin Hee , Pollock David M. , Pollock Jennifer S. , Harris Ryan A.
Published: June 2021

Individuals exposed to adverse childhood events (ACE) have an increased risk of developing cardiovascular disease in adulthood. In addition, low heart rate variability (HRV) is associated with an increased risk of coronary heart disease and is an independent predictor of mortality. The HRV response to acute stress, such as the cold pressor test (CPT), provides insight into autonomic function. Whether or not ACE impacts autonomic function during the CPT has yet to be determined.

PURPOSE

To determine whether ACE influences HRV during the CPT.

METHODS

12 adult participants (aged 34±5 years) volunteered for this study, half of which were classified as HI‐ACE (ACE score ≥ 4; n=6) and the other half as NO‐ACE (ACE score = 0; n=6). All participants underwent a CPT protocol which consisted of a 5 min baseline, 3 min of right hand submersion in ice water (~2°C), and a 5 min recovery period. HRV was determined using inter‐beat intervals and calculation of the root mean square of successive differences (rMSSD). In addition, hemodynamic parameters including heart rate (HR), cardiac index (CI), mean arterial pressure (MAP), and total peripheral resistance index (TPRI) were measured throughout the CPT protocol using infrared fingertip plethysmography (Finapres NOVA).

RESULTS

Demographics were similar between groups and no differences (all p>0.05) were observed in baseline values of HR (61±9 vs.65±5 bpm), SBP (125±9 vs. 124±15 mm Hg), or DBP (78±8 vs. 71±10 mm Hg). rMSSD was significantly lower during the CPT compared to both baseline (p=0.032) and recovery (p=0.006) in NO‐ACE. No significant changes in rMSSD in response to CPT were observed in HI‐ACE. The hemodynamic (HR, CI, MAP, and TPRI) response to CPT was similar (all p>0.05) between ACE groups.

CONCLUSION

These data indicate that autonomic function, represented by rMSSD in response to CPT, is blunted in individuals who have experienced childhood adversity compared to those who have not. Given that the HI‐ACE group presented as normotensive and otherwise apparently healthy, future studies are needed to better understand contributors to autonomic dysfunction in this cohort.

Support or Funding Information

Supported in part by NIH/NHLBI P01HL069999 (DMP, JSP, RAH).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Acute Beetroot Juice Supplementation on Power, Velocity, and Repetitions to Failure during Resistance Exercise
Authors: Ballmann Christopher G , Martin Mary Page , Rogers Rebecca R , Williams Tyler D
Published: June 2021

PURPOSE

The purpose of this study was to examine the effects of acute beetroot juice (BRJ) supplementation on power, velocity, and repetitions to failure (RTF) during bench press exercise.

METHODS

Resistance‐trained male participants were recruited for this study. In a within groups counterbalanced study design, participants were supplemented with either 70 ml of BRJ or placebo (Black‐currant juice; PL) two hours before exercise. During each exercise trial, participants began by completing 2 sets × 2 reps of bench press at 70% 1‐RM with maximum explosive intent. Power and velocity of barbell movement was measured using a linear position transducer. Participants then completed 3 sets × RTF at 70% 1‐RM separated by 2 minutes of rest between each set. Maximum mean power, velocity, and total RTF were analyzed.

RESULTS

Velocity of barbell movement was significantly higher with BRJ when compared to PL (p=0.011; ES=1.3). Furthermore, power of barbell movement was significantly higher with BRJ versus PL (p=0.015; ES= 0.58). Total RTF was not different with BRJ versus PL (p=0.091; ES= 0.55).

CONCLUSION

Results indicate that acute BRJ supplementation positively impacts both velocity and power during bench press exercise.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Influence of Caffeine and the −163 A>C CYP1A2 Polymorphism on Peak and Mean Power during a Wingate Test
Authors: Smith Caleb R. , Eberly Julia , Steckbeck Rachel J. , Wright Madison R. , Shenk Brian , Shin Michael , Kieffer H. Scott
Published: June 2021

The influence of the cytochrome P450 enzymes, specifically a polymorphism of the CYP1A2 genotype, following caffeine ingestion has been shown to influence aerobic endurance; however, the effect on short‐term anaerobic performance is inconclusive. Individuals with the AA variant are responders to caffeine and those with the AC/CC variant are non‐responders.

PURPOSE

To examine the effects of caffeine and specific CYP1A2 genotype on anaerobic performance.

METHODS

10 subjects completed two 30 second Wingate Anaerobic Tests (WAnT30) (resistance = 0.075 kg•BW−1) on the Velotron that were separated by 2 to 7 days. Relative peak power (PP) and relative mean power (MP) were computed by the Velotron software. An oral bolus of caffeine (CAF), 5mg•kg−1, or placebo (PLA), maltodextrin, was given in a randomized and counterbalanced design 60 min prior to testing. Buccal epithelial cells were collected via a mouth rinse of 0.9% NaCl. Genomic extraction was obtained using QiAmp Mini spin columns and cell lysing with proteinase k, followed by PCR amplification with Fast Taq. The restriction enzyme (ApaI) was used to cut fragments. Cut and uncut samples underwent electrophoresis in 1% agarose gel and ultraviolet light photography identified genotype. The data was analyzed using a 2 (condition) × 2 (CYP) ANOVA with repeated measures (p>0.05).

RESULTS

5 people were AA and 5 people were AC/CC. The results revealed that CAF elicited no ergogenic effects. The main effect of condition, PLA versus CAF, showed no significant difference for PP or MP (p = 0.49). The main effect of CYP1A2, AA or AC/CC, did not reveal power differences for PP or MP (p = 0.96). Follow‐up pairwise comparisons between PLA to CAF for PP (W•kg−1) showed non‐significant D's of 1.17% in AA (10.3 and 10.42) and −0.38% for AC/CC (10.36 and 10.46, respectively). Likewise, MP resulted in non‐significant D's of 3.66% for AA (8.2 and 8.5 W•kg−1, respectively) and 2.24% for AC/CC (8.3 and 8.5, W•kg−1 respectively).

CONCLUSION

Caffeine did not produce an ergogenic effect for anaerobic exercise, regardless of an individual's CYP1A2 variant. However, the larger percent increases, specifically in MP, suggest that further research should be conducted, such as increasing sample size and identifying confounding variables such as other receptor sites that may interact with caffeine.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Lasting alterations to the exercise ventilatory response in adult survivors of prematurity
Authors: Welper Hannah M , Farrel Emily , Pegelow David , Jacobson Joseph , Baker Kim , Dagle John , Eldridge Marlowe , Bates Melissa
Published: June 2021

Introduction

We previously published that the ventilatory drive in adult survivors of prematurity is impaired in hypoxic conditions. Previously studies in adult survivors of prematurity demonstrate impairments in expiratory flow that limit ventilation during exercise. However, ventilatory drive during exercise has not been explored. Therefore, the purpose of this study was to evaluate the ventilatory drive during exercise, including exercise in hypoxia. We hypothesized that the ventilatory drive (VE/VCO2) to exercise would be limited in individuals born premature and not further impacted by hypoxia.

Methods

Prematurely born adults (age 19–21) from the Newborn Lung Project cohort participated in two graded exercise tests breathing either 21% (normoxia) or 12% (hypoxia) oxygen. The term‐born control group was well‐matched in terms of sex, height, weight, baseline pulmonary function, and VO2max. We measured arterial blood gases, metabolism and ventilation at each workload to determine the ventilatory response to normoxic and hypoxic exercise.

Results

In normoxic exercise, adults born prematurely have overall increased minute ventilation, compared to controls, explained by an increased frequency that compensated for their limited tidal volume. VE/VCO2 was also greater, suggesting reduced ventilatory efficiency. This is can be explained by the lower blood pH during exercise. In hypoxic exercise, the ventilatory drive in adults born prematurely is more similar to the control.

Conclusion

We demonstrate the existence of a lifelong ventilation phenotype associated with prematurity that, contrary to our hypothesis, includes decreased ventilatory efficiency (increased VE/VCO2) and decreased blood pH. Prematurely‐born adults compensate for poor chemoreceptor function in hypoxic exercise via mechanisms currently being investigated by our group.

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 blue light blocking glass on clock gene expression, melatonin secretion and sleep quality in humans
Authors: Sato Maki , Oishi Sayo , Kodama Chihiro , Inukai Yoko , Kamiya Mika , Nishimura Naoki , Kanikowska Dominika , Iwase Satoshi
Published: June 2021

Light has a strong effect on the circadian rhythm. Blue light at night has a negative effect on melatonin secretion and sleep quality. Recently, a smart phone is popularly used in the whole day even including night, resulting in the increased rate of insomnia and difficulties of quality of sleep. In the present study, we investigated that the effect of blue light blocking glass on clock gene expression, melatonin secretion and sleep quality in humans. Seven men participated in this study for overnight from 18:00 h to 8:00 h of next day. Each subject underwent two conditions with and without wearing blue light blocking glass on a different day. Subjects sat in front of 5000 lux fluorescent and blue light lumps until sleep at 0:00 h in a climatic chamber set at 26°C and 50% relative humidity. Subjects were measured Electrocardiogram during the experiment and Electroencephalogram during the night. Saliva samples were collected at 20:00 h, 23:30 h, 6:00 h and 8:00 h. Total RNA was isolated from saliva sample and was measured the clock gene expressions of Clock, Bmal1, Per1 and Cry1 by real‐time PCR. Clock gene expression were not significantly different between the two groups. The melatonin concentrations were not significantly different between the two groups. Total percentage of slow‐wave sleep and the sleep latency to stage 3 were not significantly different with both conditions. Our results suggested that blue blocking glass have individual effects under strong light by 5000 lux.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effect of Mild Heat Stress on Event‐Related Potential in the Elderly
Authors: Ota Akemi , Takeda Ryosuke , Imai Daiki , Kawai Eriko , Saho Kosuke , Morita Emiko , Suzuki Yuta , Yokoyama Hisayo , Okazaki Kazunobu
Published: June 2021

Background

The cognitive function is generally decreased with healthy aging. The cognitive processing evaluated by electroencephalogram event‐related potentials (ERPs) has been reported to be decreased with heat stress in young individuals, while remained unclear in the elderly. Therefore we tested the hypothesis that the cognitive processing would be decreased in the elderly compared with the youth during mild hyperthermia.

Methods

Five elderly and 11 young healthy men underwent auditory oddball paradigms under two thermal conditions; Normothermia (NT) and mild hyperthermia (HT; esophageal temperature, +1°C) with lower legs immersion of 42°C and with water perfusion suits of 45°C. The reaction time by pushing a button and the latency and amplitude of P300 component to the auditory oddball paradigms were measured.

Results

The reaction time was decreased during HT compared to NT (P < 0.05). In contrast, the latency of the P300 component did not change with heat stress in both age groups. The amplitude of P300 component decreased in the elderly group while increased in the young group with heat stress (age x thermal condition, P < 0.05), and the amplitude during HT was lower in the elderly than the young group (P < 0.05).

Conclusions

Mild heat stress reduced the cognitive processing evaluated by ERPs in the elderly while not in the young subjects.

Support or Funding Information

This study was supported in part by a Grant‐in‐Aid for Scientific Research (17K01656), from Japan Society for the Promotion of Science for Akemi Ota

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Caffeine Prevents Prostaglandin E1‐induced Disturbances in Respiratory Neural Control: Therapeutic Implications for Infants Treated for Congenital Heart Disease
Authors: Mitchell Lisa , Mayer Catherine , Raffay Thomas , DiFiore Juliann , MacFarlane Peter
Published: June 2021

Prostaglandin E1 (PGE1) is frequently infused in human neonates with congenital heart disease to maintain ductus arteriosus patency; however this can cause central apnea which may necessitate endotracheal intubation. Caffeine is commonly used in the neonatal intensive care unit as a treatment for apnea of prematurity, and is believed to exert its effects primarily through adenosine receptor antagonism. In a prior study in preterm infants, a higher incidence of intermittent hypoxia events (a surrogate measure of apnea) correlated with an augmented ventilatory response to acute hypoxia (HVR). In the present study we sought to elucidate whether PGE1 enhances the HVR in 10‐day old rats and whether this effect would be prevented via pre‐treatment with caffeine. Rat pups received intraperitoneal injections of PGE1 (1μg/kg) and two hours later the HVR (10% O2, 5 min) was assessed using whole‐body plethysmography. PGE1 increased the HVR relative to saline (control) animals. Pre‐treatment with caffeine (5mg/kg) 1 hour prior to PGE1 injection prevented the increased HVR, as did pre‐treatment with MSX‐3 (100 mg/kg; a selective adenosine 2A antagonist). We propose that PGE1 exerts adenosine‐mediated effects on brainstem mechanisms of respiratory control, which may lead to destabilization of breathing in human infants being treated for congenital heart disease. Caffeine could be a convenient treatment to prevent respiratory instability in infants receiving PGE1 infusions.

Support or Funding Information

Department of Pediatrics FRAP award

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inspiratory pressure‐generating capacity is preserved during ventilatory and non‐ventilatory behaviours despite profound diaphragm muscle weakness in young adult dystrophic (mdx) mice
Authors: Burns David P , Murphy Kevin H , Lucking Eric F , O'Halloran Ken D
Published: June 2021

Diaphragm dysfunction is recognized in the mdx mouse model of muscular dystrophy, however there is a paucity of information concerning the neural control of dystrophic respiratory muscles. In young adult (8 weeks of age) male wild‐type and mdx mice, we assessed ventilatory capacity, neural activation of the diaphragm and external intercostal (EIC) muscles and inspiratory pressure‐generating capacity during ventilatory and non‐ventilatory behaviours. We hypothesized that respiratory muscle weakness is associated with impaired peak inspiratory pressure‐generating capacity in mdx mice.

Ventilatory responsiveness to hypercapnic hypoxia was determined in conscious mice by whole‐body plethysmography. Diaphragm isometric and isotonic contractile properties were determined ex vivo. In anaesthetized mice, thoracic oesophageal pressure, and diaphragm and EIC electromyogram (EMG) activities were recorded during baseline conditions and sustained tracheal occlusion for 30–40s.

Despite substantial diaphragm weakness, mdx mice retain the capacity to enhance ventilation during hypercapnic hypoxia. Peak volume‐ and flow‐related measures were also maintained in anaesthetized, vagotomized mdx mice. Peak inspiratory pressure was remarkably well preserved during chemoactivated breathing, augmented breaths, and maximal sustained efforts during airway obstruction in mdx mice. Diaphragm and EIC EMG activities were lower during airway obstruction in mdx compared with wild‐type mice.

We conclude that ventilatory capacity is preserved in young mdx mice. Despite profound respiratory muscle weakness and lower diaphragm and EIC EMG activities during high demand in mdx mice, peak inspiratory pressure is preserved, owing to sufficient compensatory recruitment of accessory muscles beyond the primary muscles of inspiration. We suggest that a loss of compensation during progressive disease, combined with diaphragm dysfunction, underpins the development of respiratory system morbidity in dystrophic diseases.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Protrusion Strength Training of the Tongue in Adult Humans
Authors: Davenport Paul Wesley , Berry Richard B , Vann William J , Kizza Rosie , Purdy Susan , Ryals Scott
Published: June 2021

Upper airway patency is regulated by the integrated function multiple muscle system. Of particular importance is the position, strength and tone of the tongue. Tongue protrusion moves the tongue anterior in the mouth and expands the pharyngeal passage. Reduced tongue protrusion strength and tone may affect swallow and breathing. We hypothesized that the tongue can be strengthened to increase protrusion force. A placebo controlled study was performed in adult volunteers. A unique spring‐loaded device was constructed to provide protrusion strength training. The pre‐treatment maximum tongue protrusion force (MTPF) was measured and subjects randomly assigned to placebo or trained groups. The subjects were provided the device with low spring constant (placebo) or high spring constant (trained). The subjects performed a once‐daily tongue protrusion exercise by placing the device in their mouth, holding the device in place with their teeth, pushing the tongue onto a spring‐loaded piston and forcing the piston 0.5–1.0 cm into the device cylinder. The subjects performed 25–35 protrusion efforts per training session, 1 training session per day, 5 days per week for 8 weeks. Post‐treatment MTPF was recorded at the completion of the 8‐week exercise protocol. The trained group exercised with the device set to 70–80% MTPF. The placebo device was approximately 15% MTPF. The MTPF significantly increased in both the placebo and trained groups. The MTPF was significantly greater (38%) for the trained group compared to the placebo group (17%). The results of this study demonstrated that tongue protrusion strength can be increased by protrusion specific exercises using a spring‐loaded device. The placebo group had a significant training effect suggesting low intensity tongue protrusion exercise will increase MTPF.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Novel Pharmacological Approach to Treat Acute Lung Injury
Authors: Qu Xinyan , Hitchinson Ben , Banerjee Avik , Zhao Shuangping , Zhang Chongxu , Gaponenko Vadim , Komarova Yulia
Published: June 2021

Acute Respiratory Distress Syndrome (ARDS) is a lung disease characterized by acute respiratory failure, morbidity, and mortality. There are no effective therapies for ARDS, and standard care remains largely supportive. Here, we offer a novel pharmacological approach to treat ARDS by inhibiting microtubule accessory factor end binding protein 3 (EB3), which contribute to vascular leakage by amplifying pathological calcium signaling in endothelial cells. We employed structure‐activity‐relationship studies by nuclear magnetic resonance to design an allosteric inhibitor of EB3 that has optimal physicochemical and biochemical properties and is suitable for future clinical applications. Using standard methods for backbone rigidification and non‐proteinogenic amino acids, we have designed and tested sixty‐one drug‐like compounds, twenty‐six of which demonstrate remarkable similarity in binding the C‐terminus of EB3. Further screens using a cell‐based system identified four compounds with cell‐penetrating properties. These compounds are potent in inhibiting agonist‐evoked calcium release from endoplasmic reticulum stores and mitigating the effect of pro‐inflammatory mediators on the endothelial barrier. Based on in vitro stability in human blood plasma, we selected one lead and two backup compounds for further in vivo pre‐clinical studies. All three compounds inhibit endothelial capillary leakage in mice challenged with IV administration of PAR‐1 agonist peptide. Our studies establish a workflow for rational drug design to allosterically modulate EB3 function. Novel drug‐like compounds are stable and efficacious in treating lung endothelial microvascular hyperpermeability and may provide an important future clinical use in treating pulmonary edema associated with ARDS.

Support or Funding Information

This project has been funded in whole with Federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN268201700007C to YAK.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Fos‐CreER Based Genetic Mapping of Forebrain Regions Activated by Acupuncture
Authors: Guo Zhi‐Ling , Lin Xiaoxiao , Samaniego Tracy , Isreb Alexander , Cao Stacey , Malik Shaista , Xu Xiangmin
Published: June 2021

Acupuncture is an important practice used in traditional Chinese medicine (TCM), and it generates therapeutic effects through the insertion of thin needles through the skin at specific acupoint(s) in the body to stimulate sensory nerves. Many of the acupoints have multiple therapeutic indications. Using rodent models, we have found that manual acupuncture (MA) at the Neiguan (P6) acupoint overlying median nerve inhibits excitatory cardiovascular reflex responses through its influence on specific regions involving in the regulation of autonomic nervous system in the brain stem. However, in TCM, it is also the acupoint for treating nausea and headaches. It is largely unknown whether MA at this acupoint activates neurons in the brain regions beyond the brain stem. To further understand neural mechanisms underlying acupuncture effects, in this study, we map P6 specific neural activation by MA in the forebrain using a Fos‐CreER based mouse genetic strategy. Identification of c‐Fos expression is achieved using the Fos‐CreER mice crossed with the Cre reporter Ai9 mice to express the tdTomato fluorescent protein. This genetic method allows for enhanced sensitivity and efficiency compared to conventional immunohistochemical staining. Specifically, at 30 min following 4‐OHT (a metabolite of tamoxifen; i.p., 1 mg/per mouse) administration, MA or sham‐MA at P6 were conducted under anesthesia with ketamine: xylazine (75:10 μg/g, i.m.). MA was performed by gentle manual rotation of the acupuncture needle at a frequency of □2 Hz for 3 min every 10 min during a 30 min period. Identical procedures without the rotation of the needle at P6 were carried out in the mice treated with sham‐MA. With tissue collection after ten days, we observed that MA at P6 markedly increases c‐Fos/tdTomato+ neuronal labels in a number of the forebrain regions, compared to the sham‐MA group (n=5 in each group). These regions include accumbens nucleus, caudate putamen, bed nucleus of the stria terminalis, amygdaloid nucleus, ventral posterior division of the thalamic nucleus, paraventricular hypothalamic nucleus, arcuate hypothalamic nucleus, primary and secondary sensory cortex, ectorhinal cortex, dorsolateral entorhinal cortex, and claustrum. These data indicate that MA at P6 activates neurons in relatively broad brain networks beyond the brain stem, suggesting that acupuncture at this acupoint has the potential to influence physiological functions, associated with autonomic and non‐autonomic nervous systems through its effects on multiple brain regions.

Support or Funding Information

NIH NCCIH AT009347 and NIH MH113026

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
V3 neurons regulate sensory transmission as well as locomotion
Authors: Lin Shihao , Lucas‐Osma Ana M , Li Yaqing , Hari Krishnapriya , Fouad Karim , Fenrich Keith K , Bennett David James
Published: June 2021

It has been shown that the V3 spinal interneurons contribute to locomotion. Here we examined the role of V3 interneurons on sensory transmission. Using confocal microscopy, we found that V3 interneurons receive monosynaptic contacts from sensory afferents and also project monosynaptically back to sensory afferents. Furthermore, intracellular recording of afferents revealed that optogenetic activation of V3 neurons monosynaptically produce a primary afferent depolarization (PAD), with a large NMDA component as well as a classic GABA component. This PAD excites afferents, produces spiking, and in turn drives motoneurons. Furthermore, following V3 neuron activation, subsequent direct activation of sensory afferents caused much attenuated reflexes, likely because the reflex and PAD pathways employ shared V3 neurons. These results suggest that V3 neurons provide an anticipatory activation of afferents (afferent copy). This prepares the spinal cord for actual sensory input and attenuates unwanted sensory evoked motor output during voluntary movements like walking.

Support or Funding Information

Canadian Institutes of Health Research; National Institutes of Health

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neurotransmitter Receptor Antagonism Inhibits the Sea Urchin Righting Response
Authors: Shelley Chris , Dyar Andrew , Schieber Marquis
Published: June 2021

The deuterostome superphylum comprises the chordates, which includes all vertebrates, echinoderms (including sea urchins and sea stars), and hemichordates (acorn worms). Despite the close phylogenetic relationship between invertebrate echinoderms and vertebrates, the understanding of echinoderm neurobiology lags far behind that of many other invertebrate species. To investigate molecular components of echinoderm behavior, we used the righting response, in which an inverted sea urchin will use its tube feet and spines to right itself, as a behavioral assay. Using purple sea urchins (Strongylocentrotus purpuratus) we demonstrate that immersion in drug solution is a simple and effective drug administration route. Using the drug immersion procedure, we show that the sea urchin righting response is inhibited in a dose‐dependent manner by the nicotinic acetylcholine receptor antagonist hexamethonium and also affected by the GABAA receptor antagonist bicuculline. In addition, decreasing the concentration of extracellular Ca2+ also inhibited the righting response. These data start to elucidate the receptor systems involved the control of sea urchin motor activity.

Support or Funding Information

Funding was provided by the University of the South Conduff Fund and the University of the South Kresge Fund.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Enhancement of apneic reflex induced by sumatriptan: Role of bronchopulmonary C‐fibers in rats
Authors: Chan Nai‐Ju , Chen Yueh‐Yin , Lin You Shuei , Hsu Chun‐Chun
Published: June 2021

Sumatriptan (Imigran®), an agonist of 5‐hydroxytryptophan (5HT)1B and 5HT1D receptors, is widely and effectively used to alleviate migraine headaches. Two of the most frequent side effects reported by patients are somatic hyperalgesia and chest discomfort. The chest syndromes are represented by chest tightness and dyspnea. Bronchopulmonary sensory C‐fibers innervate all levels of respiratory tract. Stimulation of the sensory fibers elicit airway reflexes including bronchoconstriction, shortness of breath, and dyspnea. This study was carried out to determine the effect of intravenous infusion of sumatriptan on sensitivity of ventilatory reflexes and bronchopulmonary sensory C‐fibers. In anesthetized, spontaneously breathing Brown‐Norway rats, the apneic response to right‐atrial injection of capsaicin was markedly enhanced 3 min after termination of sumatriptan infusion, which returned toward baseline within 80 min. In contrast, infusion of vehicle of sumatriptan failed to cause the enhancing effect. In our electrophysiological study, sumatriptan infusion did not influence the baseline activity of bronchopulmonary sensory C‐fibers in open‐chest, and artificially ventilated rats. However, these C‐fiber responses to right atrial injection of capsaicin were markedly potentiated 3 min after termination of sumatriptan infusion. The results suggest that sumatriptan enhances the excitability of bronchopulmonary sensory C‐fibers, which may, in turn, contribute to airway hypersensitivity.

Support or Funding Information

Supported in part by grants TMU105‐AE1‐B17, MOST‐107‐2320‐B‐038‐041 and MOST‐107‐2320‐B‐038‐049‐MY3

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Serum Glucocorticoid Kinase 1 (SGK1) Expression in Dendritic Cells Contributes to Salt‐Induced Hypertension in Mice
Authors: Birch Wayne , Van Beusecum Justin P , Barbaro Natalia R , MacDowell Zoe , Aden Luul A , Xiao Liang , Pandey Arvind K , Itani Hana A , Harrison David G , Kirabo Annet
Published: June 2021

Salt‐sensing mechanisms in hypertension involving the kidney have been well studied; however, recent studies suggest that immune cells can sense Na+. Antigen presenting cells like dendritic cells (DCs) critically modulate inflammation by activating T cells and producing cytokines. We recently found that sodium enters DCs through amiloride‐sensitive channels including the alpha and gamma subunits of the epithelial sodium channel (ENaCαγ) and mediates NADPH oxidase‐dependent formation of immunogenic isolevuglandin (IsoLG)‐protein adducts leading to inflammation and hypertension. Here we describe a novel pathway in which the salt sensing kinase serum/glucocorticoid kinase 1 (SGK1) in DCs mediates salt‐induced assembly of ENaCαγ and promotes salt‐sensitive hypertension by activation of the NADPH oxidase and formation of IsoLG‐protein adducts. Mice lacking SGK1 in CD11c+ cells were protected from renal inflammation, endothelial dysfunction and developed blunted hypertension during the high salt feeding phase of the N‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME)/high salt model of salt‐sensitive hypertension. DCs treated with high salt exhibited increased expression of ENaCγ which co‐immunoprecipitated with ENaCα. This was associated with increased activation and expression of various NADPH oxidase subunits. Genetic deletion or pharmacological inhibition of SGK1 in DCs prevented the high salt induced expression of ENaCγ (0.04±0.04, WT, 0.05±0.04, WT plus HS and 0.06±0.05, KO plus HS, p<0.01) and ENaCα (0.29±0.20, for WT, 0.28±0.19, for WT plus HS and 0.30±0.24, for KO plus HS, p<0.01). These results indicate that expression of SGK1 in DCs contributes to the pathogenesis of salt‐sensitive hypertension by stabilizing expression of ENaCαγ leading to activation of NADPH oxidase.

Support or Funding Information

This work was supported by the American Heart Association grants POST290900 and SFRN204200, and National Institutes of Health grants K01HL130497, R01HL125865, and R01HL039006.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mucin 1 is Necessary for TrpV5 Localization in the Kidney's Distal Convoluted Tubule and Normal Bone Architecture
Authors: Ray Evan C. , Al‐Bataineh Mohammad , Marciszyn Allison L. , Poland Paul , Santucci Christopher , Robinson Lisa , Blair Harry C. , Hughey Rebecca P. , Kleyman Thomas R.
Published: June 2021

Mucin 1 (Muc1 in mice and MUC1 in humans) is a heavily glycosylated transmembrane protein expressed in numerous epithelia. Muc1 interacts with other glycoproteins via interaction with galectins, which bind β‐galactoside sugars. Genome‐wide association data suggest a link between MUC1 polymorphism and bone density. MUC1 exogenously expressed in cultured cells physically interacts with calcium‐selective ion channel TRPV5, increasing cell surface expression and activity in a galectin 3‐dependent fashion. TrpV5 knock‐out (KO) mice exhibit impaired reabsorption of filtered Ca2+ in the kidney's distal convoluted tubule (DCT), resulting in hypercalciuria and diminished trabecular and cortical bone thickness. We hypothesize that interaction between Muc1 and TrpV5 is necessary for normal Ca2+ homeostasis and bone architecture. We examined density and architecture in Muc1 KO mice using μCT of lumbar vertebrae. Male Muc1 KO mice exhibit reduced lumbar vertebral cortical and trabecular thickness, with increased surface area/volume. Muc1 KO mice exhibit similar whole‐blood ionized Ca2+ levels, but increased kidney 1‐α‐hydroxylase levels, suggestive of bodily Ca2+ depletion. We observe that TrpV5 is mis‐localized in the DCT of Muc1 KO mice, suggesting that impaired renal tubular Ca2+ reabsorption may contribute to this Ca2+ depletion. Additionally, TrpV5 is mis‐localized in the DCT in galectin‐3 KO mice, consistent with a role for galectin 3 in mediating Muc1‐TrpV5 interaction. Taken together, these findings suggest that Muc1 plays a role in bodily Ca2+ homeostasis and bone physiology by enhancing cell surface expression of TrpV5.

Support or Funding Information

NIDDK K08 DK110332, K01 DK109038, P30 DK079307

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