bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carotid Artery Structure during and after Long‐Duration Space Flight
Authors: Lee Stuart M. C. , Martin David S. , Laurie Steven S. , Ribeiro L. Christine , Smith Scott M. , Zwart Sara R. , Stenger Michael B. 
Published: November 2023

Space flight missions may expose astronauts to increased risk of oxidative stress and inflammatory damage induced by a variety of sources, including radiation, psychological stress, reduced physical activity, diminished nutritional status, and hyperoxic exposure during extravehicular activity. Given that evidence exists that these factors can accelerate the development of atherosclerosis, the purpose of this investigation is to determine whether long‐duration space flight (>4 months) on the International Space Station results in structural changes in the carotid artery.METHODSCarotid artery intima‐media thickness (cIMT) and diameter during systole (Ds) and diastole (Dd) were measured using standard ultrasound (VividQ, GE Healthcare) in 10 astronauts (9 M, 1 F) approximately 180 and 60 days before launch, at approximately 15 (FD15) and 60 days of flight (FD60), within two weeks before landing (R‐14), and within one week after landing. Pre‐ and post‐flight measures were obtained after the subjects had been supine for at least 20 min. Inflight measures were acquired by trained astronauts while being guided by an expert sonographer on the ground using telemedicine techniques. Carotid artery distensibility coefficient was calculated (cDC = (Ds2−Dd2)/(PP·Dd2); Gepner et al., Stroke 45: 48–53, 2014). Pre‐flight data were averaged to represent baseline. Results were analyzed using one‐way repeated measures ANOVA.RESULTSCarotid artery diameters during systole (Ds FD15: 7.6 ± 0.4; FD60: 7.6 ± 0.4; R‐14: 7.7 ± 0.4 mm; mean ± SD) and diastole (Dd FD15: 7.2± 0.3; FD60: 7.3 ± 0.4; R‐14: 7.3 ± 0.5 mm) were significantly greater during space flight than pre‐ (Ds: 7.3 ± 0.4; Dd: 6.9 ± 0.4 mm) and post‐flight (Ds: 7.4 ± 0.4; Dd: 7.1 ± 0.5 mm). There was a main effect of time on cIMT, but post‐hoc analyses did not reveal significant difference from pre‐flight (Pre: 0.58 ± 0.09 mm) at any time point (FD15: 0.58 ± 0.14; FD60: 0.54 ± 0.09; R‐14: 0.54 ± 0.09; Post: 0.62 ± 0.10 mm). Although pre‐flight cDC (0.0028 ± 0.0011/mmHg) was not different than in‐flight (FD15: 0.0023 ± 0.0011; FD60: 0.0020 ± 0.0008; R‐14: 0.0023 ± 0.0012/mmHg), post‐flight cDC (0.0019 ± 0.0010/mmHg) was significantly less than pre‐flight.CONCLUSIONSAlthough the carotid artery was distended chronically during space flight and cDC was decreased in the week after landing, in these astronauts pathological remodeling of this vessel was not evident.Support or Funding InformationSupported by the NASA Human Research Program
ATP‐sensitive K+ Channel Inhibition via Glibenclamide Does Not Increase Lumbar or Renal Sympathetic Nerve Discharge in Healthy Rats
Authors: Colburn Trenton D , Holdsworth Clark T , Craig Jesse C , Hirai Daniel M , Montgomery Shawnee , Kenney Michael J , Musch Timothy I , Poole David C 
Published: November 2023

ATP‐sensitive K+ (KATP) channels contribute to exercise‐induced hyperemia and O2 delivery in skeletal muscle. KATP channel inhibition via glibenclamide (GLI) increases mean arterial pressure (MAP) and reduces blood flow to the rat hindlimb during exercise: demonstrating greater reductions in oxidative compared to glycolytic muscles. Whether this control via KATP channels is mediated locally within skeletal muscle by decreased vascular hyperpolarization or alternatively by increased sympathetic nerve activity instigated within the rostral ventrolateral medulla (Guo et al. J. Pharmacol. Exp. Therapeut. 338:458–65, 2011) or other cardiovascular control centers is unknown. We hypothesized that KATP channel inhibition via intravascular infusion of GLI would increase MAP without increasing lumbar and renal sympathetic nerve discharge (SND). In 12 male anesthetized Sprague‐Dawley rats, lumbar (n=8) and renal (n=8) nerves were isolated for measurement of SND. Following 60 min stabilization after surgery, a bolus infusion of saline (CON) was administered via the femoral vein catheter and SND, MAP (n=12), and HR (n=12) were recorded for 10 min. This protocol was then used following a bolus infusion of GLI (5 mg kg−1 in ~1 mL heparinized saline). SND was calculated as percent change from baseline (ΔSND (%)). There were no significant changes in MAP, HR, or lumbar ΔSND (%) following CON (P > 0.05 for all) and only minute 8 exhibited marginally increased renal ΔSND (%) (P < 0.05). Compared to CON, GLI increased MAP (min 3–10), reduced lumbar ΔSND (%) (min 2–10; up to 47%), and reduced renal ΔSND (%) (min 2–9; up to 36%) (P < 0.05 for all). There were no significant changes in HR due to GLI (P > 0.05). These results demonstrate that KATP inhibition produces a decrease in both lumbar and renal SND likely related to increased MAP. Therefore, reductions in exercising muscle blood flow and O2 delivery following GLI do not result from enhanced sympathetic activity; supporting that vasomotor control via KATP channels is likely mediated by local vascular effects within skeletal muscle.Support or Funding InformationNIH HL‐2‐108328
Lumbar Sympathetic Nerve Activity at Rest and During Muscle Contraction: Effects of Estrogen and Nitric Oxide
Authors: Just Timothy P , DeLorey Darren S 
Published: November 2023

Efferent sympathetic nerve activity (SNA) is critical for the control of blood pressure and peripheral vascular resistance at rest and during exercise. Nitric oxide (NO) is known to have an inhibitory effect on efferent SNA and estrogen has been shown influence NO synthase (NOS) expression and NO bioavailability. Therefore, the purpose of this study was to investigate the hypothesis that estrogen status alters SNA at rest and during muscle contraction through an NO dependent mechanism. Female Sprague‐Dawley rats were randomly assigned to OI (n=10), OVX (n=9) or OVX‐E (n=8) groups. A bilateral ovariectomy was performed in OVX rats and a placebo or time‐release 17β‐estradiol pellet (OVX‐E) was implanted subcutaneously for 4 weeks. Rats were then anesthetized and instrumented for the measurement of blood pressure and lumbar SNA (LSNA) at rest and during hindlimb muscle contraction in control, NOS blockade (L‐NAME; 10 mg·kg−1 IV), and NOS blockade with normalization of blood pressure (hydralazine; 0.01–0.06 mg·kg−1·min−1 IV) conditions. In control conditions, MAP and LSNA were similar (p>0.05) in OI, OVX and OVX‐E rats at rest. LSNA increased in response to muscle contraction in all groups and LSNA was not different in OI, OVX and OVX‐E rats during muscle contraction. NOS blockade increased (p<0.05) MAP and decreased LSNA by similar magnitudes (p>0.05) in OI, OVX and OVX‐E rats at rest and during exercise. Infusion of hydralazine in the presence of NOS inhibition returned MAP to levels observed at rest and during muscle contraction in the control condition in all groups. LSNA was not different (p<0.05) in OI, OVX, OVX‐E rats at rest and during muscle contraction in the presence of NOS inhibition and hydralazine. These data suggest that estrogen status does not alter efferent sympathetic nerve activity directed to skeletal muscle at rest or during exercise. Furthermore, these data suggest that the effects of systemic NOS blockade on LSNA are not dependent on estrogen status.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada (NSERC), Canadian Foundation for Innovation, and Alberta Advanced Education and Technology.
Combined Influences of Subsystolic Regional Circulatory Occlusion and Pedal Rate on the Exercise Pressor Reflex in Healthy Adults
Authors: Villarraga Nico , Van Iterson Erik H. , Randall Nicholas , Ziegler Briana , Olson Thomas P. 
Published: November 2023

IntroductionThe contribution of metabolic vs mechanical stimuli related to the group III/IV afferent‐mediated exercise pressor reflex (EPR) remains incompletely understood. High pedal frequency during cycling increases type II muscle fiber recruitment and may contribute to increased anaerobically‐mediated metabolic byproduct accumulation. This may lead to an augmented rise in systolic blood pressure (SBP) and, hence, EPR in humans. Thus, we hypothesized, 1) Mean arterial pressure (MAP) will be increased during exercise with SubRCO vs without NoRCO irrespective of pedal frequency, and 2) MAP will be augmented further during exercise with SubRCO at high pedal frequencies.MethodsHealthy adults (N=13; 46% men; age 36±19 yr; BMI 24±4 kg/m2) participated in 2 study visits, each consisting of 2 sessions of fixed load (20 W) recumbent cycle ergometry with bilateral upper thigh pressure tourniquets for 8 min at a fixed pedal frequency of 35 (LOW) or 100 (HIGH) rpm (randomized). Cuffs remained at 0 mm Hg for the first 3 min (CTL), and were then randomized to 0 mm Hg (NoRCO) or 90 mm Hg (SubRCO) for the final 5 min of exercise. SBP and diastolic blood pressure (DBP) were measured via manual sphygmomanometry at the end of CTL and end‐exercise (END). MAP was calculated as (SBP + 2 * DBP)/3.ResultsThere were no between or within condition differences at CTL for MAP (P>0.05). In contrast, for between SubRCO and NoRCO differences at END, MAP was increased in SubRCO vs NoRCO in both HIGH (106±12 vs 92±13 mm Hg, respectively) and LOW (94±9 vs 85±8 mm Hg, respectively) (P<0.05). At END, MAP was increased in HIGH vs LOW within both SubRCO and NoRCO (P<0.01). Within both NoRCO (129 ± 18 vs 117 ± 11 mm Hg) and SubRCO (125 ± 15 vs 113 ± 10 mm Hg) at CTL, SBP was increased in HIGH vs LOW, respectively (P<0.01). At CTL, there were no between SBP NoRCO vs SubRCO differences in HIGH or LOW. Within SBP differences for NoRCO (134 ± 19 vs 113 ± 11 mm Hg) and SubRCO (147 ± 20 vs 127 ± 12 mm Hg) in HIGH vs LOW persisted to END, respectively (P<0.01). SBP increased at END vs CTL within SubRCO for both HIGH and LOW (P<0.02), but not within NoRCO (P>0.05). Lastly, SBP increased in SubRCO vs NoRCO at END in both HIGH and LOW (both P<0.01). There were no differences for DBP at any time point (P>0.05).ConclusionThese data support our hypothesis that, independent of pedal frequency, SubRCO provokes increased MAP during fixed‐load submaximal exercise as a function of increased SBP. However, high pedal rate accompanied by SubRCO results in exaggerated SBP‐mediated increased MAP. These data contribute to an improved understanding of the stimuli that activate group III/IV afferents during exercise in humans.Support or Funding InformationNHLBI RO1 HL126638; AHA 16POST30260021
Functional Sympatholysis is Impaired in End‐stage Renal Disease
Authors: Downey Ryan , Lee Ho Lim , Liao Peizhou , DaCosta Dana , Park Jeanie 
Published: November 2023

Chronic renal failure patients have reduced exercise tolerance contributing to increased cardiovascular risk. Reflex activation of sympathetic nervous activity (SNA) during exercise increases cardiac output and vasoconstricts nonworking skeletal muscle. However, within exercising skeletal muscle, local metabolites, such as nitric oxide, are generated that oppose SNA‐mediated vasoconstriction to preserve blood flow and oxygenation within the working muscle, termed functional sympatholysis. We hypothesized that chronic kidney disease (CKD) and end‐stage renal disease (ESRD) patients requiring chronic hemodialysis have impaired functional sympatholysis resulting in reduced oxygenation of exercising muscle which could contribute to exercise dysfunction. Muscle oxygen tissue saturation index (TSI) was measured in 33 subjects (13 Controls, 10 CKD, 10 ESRD) using near‐infrared spectroscopy (NIRS) positioned over the flexor digitorum profundus muscle in the forearm. Changes in muscle TSI were calculated as a percentage of total labile signal (TLS) defined as muscle TSI at the point of maximum deoxygenation during arterial occlusion. Lower‐body negative pressure (LBNP) was applied at −20 mmHg to induce an increase in SNA without causing arterial blood pressure changes. Continuous measurements were made at baseline, during LBNP, and during LBNP with concomitant rhythmic handgrip exercise performed at 30% of maximum voluntary contraction. Baseline muscle TSI was significantly lower in ESRD compared to controls and CKD (Control, 68.25±1.25%; CKD, 67.88±1.10%; ESRD, 61.80±1.74%; p=0.004). There was a reduction in muscle TSI in all groups during SNS activation induced by LBNP at rest. When compared to muscle TSI changes during LBNP at rest, the reduction in muscle TSI was significantly ameliorated during LBNP with handgrip exercise in controls (−15.20±3.05% vs. −5.01±2.62%, p=0.013), suggesting intact functional sympatholysis. Similarly, in CKD, compared to LBNP at rest, there was a trend towards improvement in the reduction in muscle TSI during LBNP with concomitant exercise (−15.74±7.66% vs. 2.26±4.28, p=0.062). However, there was no significant improvement in muscle TSI changes with concomitant exercise in ESRD (−11.94±2.04% vs. −6.25±1.82%, p=0.169). These data suggest that controls without kidney disease, and those with CKD not yet requiring renal replacement therapy have intact functional sympatholysis. However, ESRD patients on chronic hemodialysis have impaired functional sympatholysis that could contribute to exercise tolerance. Further studies are needed to elucidate the mechanisms underlying impaired functional sympatholysis in ESRD.Support or Funding InformationSupported by NIH HL‐098744, NIH DK‐00756, NIH GM‐000680, VA Merit I01CX001065, and Satellite Healthcare, a not‐for‐profit renal care provider.
Testing the Efficacy of β‐hydroxy‐β‐methylbutyrate (HMB) to Preserve Mitochondrial Function in Aging Drosophila Melanogaster
Authors: Callahan Damien M. , Mead Andrew F. , Maughan David W. 
Published: November 2023

IntroductionMitochondrial function (capacity for oxygen consumption and ATP production) declines with advancing age across most animal species. In striated muscle, mitochondrial dysfunction may play a role in age‐related loss of muscle mass (sarcopenia) and contractile dysfunction. β‐hydroxy‐β‐methylbutyrate (HMB), a metabolite of L‐leucine, has been shown to enhance the effects of resistance exercise and limit muscle atrophy with disuse and aging. Some data suggest an effect of HMB on enhancing mitochondrial function, a mechanism by which atrophy and contractile dysfunction might be attenuated.ObjectiveDrosophila melanogaster were used as a model organism to test the efficacy of HMB to limit age‐related declines in mitochondrial function. We tested the hypothesis that HMB supplementation would attenuate age‐related mitochondrial dysfunction in Drosophila compared with standard diet. A third group of 1‐week old controls raised on standard food served as a reference for the primary effects of age.MethodsFlies were reared in vials containing standard cornmeal fly food (Control), or standard cornmeal fly food containing calcium HMB monohydrate (10 mg/ml; HMB) and collected upon eclosion. Twenty flies per group were tested at 1‐week (Young) and 5‐weeks (Old). Flight ability was assessed the day prior to testing. Older flies were matched for flight ability in HMB and Control groups. Mitochondrial function (peak O2 consumption rate, OCR, and respiratory control ratio, RCR) was assessed in mitochondria isolated from IFM. Fly thoraces were dissected and homogenized in isolation buffer at 4°C to liberate mitochondria from the IFM. Following isolation by differential centrifugation, mitochondria were loaded by protein content (8 μg) and respiration was measured using an XF96e analyzer (Seahorse Biosciences/Agilent Technologies, Santa Clara CA). Respiration was measured under basal (pyruvate/malate) state 3 (ADP stimulated) and state 4 (oligomycin) conditions. OCR and RCR (state 3 OCR/state 4) was assessed in each group. Statistical measures were not applied to these preliminary data because a single value was obtained for each group of flies.ResultsYoung controls had higher flight scores than old flies in each group. Age‐related declines in OCR were noted in both HMB and Control (basal and state 3 OCR). Young flies had the highest OCR, followed by Old Controls and Old HMB (59.6, 22.4 and 21.1pmol/ug/min, respectively). Similarly, RCR was highest in Young (8.0) followed by Old Control (5.9) and Old HMB (4.1).ConclusionWe find a ~60% reduction in OCR with age regardless of group, suggesting HMB was not sufficient to attenuate age‐related reduction in mitochondrial function. Because measurements were made on similar quantities of mitochondria in each group, these reductions reflect qualitative reductions in mitochondrial function, an interpretation buttressed by reductions in RCR.Support or Funding InformationSupported by The UVM Foundation.
Orphan nuclear hormone receptor Small Heterodimer Partner plays a protective role in diet‐induced islet dysfunction
Authors: Park Jung Eun , Lee Mikang , Lee Yoon‐Kwang 
Published: November 2023

Our early study found that deficiency of small heterodimer partner (SHP, NR0B2) protected the mice from diet‐induced obesity due to increased fatty acid oxidation but exacerbated glucose tolerance due to impaired glucose‐stimulated insulin secretion upon a 6‐month western diet regimen. Current study explored potential roles of SHP in the development of glucose intolerance furthermore. We assessed islet function using illumina beadchip array and morphometric measurement of pancreatic sections. Beadchip array revealed that many exocrine specific genes (for example, CUB and Zona Pellucida‐Like Domains (cuzd1), pancreas specific transcription factor 1a (ptf1a), trypsin 4 (try4) and pancreatic carboxyl ester lipase (cel) etc.) were markedly down‐regulated in the islets of SHP null mice in either chow or western diet‐fed condition. However, expression of major genes involved in insulin secretion and islet function were similar between WT and SHP null mice. Results from quantitative real‐time PCR analysis agreed with majority of beadchip array results except Glut2, which was decreased in SHP null islets. Corroborating with impaired insulin secretion and lower Glut2 mRNA level, glucose‐stimulated Ca2+ influx was greatly diminished in SHP null islets. Islet size was also decreased in SHP null mice fed either diet. The observed diabetic phenotype and pancreatic exocrine insufficiency in whole body SHP−/−mice was recapitulated in the pancreas specific SHPKO (PSHPKO) mice, where SHP deletion is confirmed in both endocrine and exocrine tissues. Interestingly the lean phenotype was reproduced only in liver‐specific SHPKO mice but not in PSHPKO mice. Even though detailed underlying molecular mechanisms for the observed phenotypes by SHP deletion remain to be elucidated, current data suggest that SHP plays distinctive and tissue‐specific role in the development of obesity and diabetes.Support or Funding InformationThis work had been supported by the National Institutes of Health 344 Grant R01DK093774 (to YKL)
Short‐term Metformin and Exercise Training Effects on Strength, Aerobic Capacity, Glycemic Control and Mitochondrial Function in Burn Children
Authors: Rivas Eric , Porter Craig , Herndon David N. , Suman Oscar E. 
Published: November 2023

Metformin (M) has been shown to attenuate hyperglycemia and exercise (EX) has been shown to improve strength and aerobic exercise capacity in severely burn patients. However, it is unknown if the combination of M+EX can further improve these outcome measures and if EX alone will improve glycemic control in burn populations. This project tested the hypothesis that 6‐weeks of exercise training combined with short‐term administration of metformin (EX+M) compared to exercise alone (EX) would synergistically improve aerobic and strength exercise capacity, while improving mitochondrial respiration and glucose tolerance. Eight burned children (4 male) received EX after discharge while nine burned children (6 male) received M at 72–96 h post‐ admission with EX at discharge. Prior to EX, both groups had similar physical characteristics (means±SD; 15 ± 2y, 157.1±7cm, 50.1±11 kg, 34.7±6 lean body mass, LBM, 46±15% total body surface area burned; P>0.05), peak strength (peak torque 1.6±0.5 N‐M·KgLBM; P>0.05) peak aerobic capacity (VO2peak; 34.6±8 mlO2·kgLBM·min; P>0.05) and metabolic characteristics (fasting glucose 110.4±16 mg·dL and insulin 20.6±11 pmol·L, 75g oral glucose tolerance, OGTT, AUC for glucose 17776±3245 mg·dL·min and AUC insulin 8451±6043 pmol·L·min, 1878±151 kcal/24h resting energy expenditure, REE, and resting heart rate, HR 129±13 bpm; P>0.05). At PreEX time, mitochondrial respiration (pmol·sec·mg) was attenuated for each state: leak (−5.9±5) states 2 (−22.5±3) and 3 (−42.4±13), and oxphos (−58.9±19) in the M compared to the EX+M (each, P ≤0.02). Post‐burn injury EX training (started 1.4±0.6 mo postburn; P=0.33) and completed exercise sessions (30±11 days; P=0.71) was similar between groups. EX improved strength (change from preEX, Δ1.6±0.6 N‐M·KgLBM), VO2peak (Δ9±7 mlO2·kgLBM) and reduced fasting glucose (Δ19.3±13 mg·dL) and glucose AUC for the 75g OGTT (Δ3402±3674 mg·dL·min) in both groups (each, P ≤0.03). EX+M significantly reduced REE (Δ539±480 kcal/24h, P<0.01) while E alone did not (P=0.68). Both, EX+M and EX reduced resting HR (Δ30±23bpm; P≤0.02). EX+M increased mitochondrial respiration for each state (P≤0.05) to similar levels as EX alone (each P>0.05). These data indicate that short‐term metformin combined with exercise provides no further improvement beyond that of exercise alone in terms of strength, exercise capacity, and glycemic control. Most importantly, for the first time we show that short‐term exercise training improved glycemic control in burn patients. However, it remains unknown if a longer (1‐year administration) M treatment is needed to improve the hyperglycemia/insulinemia state in burn patients.Support or Funding InformationThis study was supported in part or totally by awards from: NIH P50‐GM060338, NIH R01‐GM56687, R01 HD049471, SHC 84080, 71008, 84090, and NIDILRR 90DP0043‐01‐00.