bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL‐6 Contributes to Exercise Induced Recovery of Hepatic Insulin Action in Obese Mice
Authors: Peppler Willem T. , MacPherson Rebecca E.K. , Panasevich Matthew R. , Meers Grace M. , Rector R. Scott , Wright David C. 
Published: November 2023

Obesity is associated with both systemic and hepatic insulin resistance. After only a single bout of exercise, the obesity‐induced impairment in hepatic insulin action is recovered; however, the biological mechanisms that underlie this phenomenon are not known. As circulating levels of interleukin‐6 (IL‐6) are increased after a single bout of exercise, we hypothesized that IL‐6 may contribute to the exercise‐induced recovery of hepatic insulin action in obese mice. To evaluate this hypothesis, we used three experimental approaches. First, C57BL/6 male mice were fed a low fat diet (LFD, 10% kcals from lard) or high fat diet (HFD, 60% kcals from lard) for 7 weeks, which led to increases in body mass, adiposity, and impaired glucose tolerance. Mice from the HFD group were then subjected to a single bout of exercise (2 hours of treadmill exercise at 15 m·min−1) or cage control, allowed to recover for 2 hours, and the liver was collected 15 minutes after IP insulin (1 U·kg1). Acute exercise recovered HFD‐induced impairments in insulin‐induced phosphorylation of protein kinase B (AKT) at serine 473 (pAKTSer473), a key insulin signaling protein. This occurred alongside increases in circulating IL‐6 and led to increases in indices of hepatic IL‐6 signaling, including phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and mRNA expression of suppressor of cytokine signaling 3 (SOCS3). Second, to determine whether IL‐6 was required for the recovery of induced‐insulin pAKT Ser473 with exercise, mice were injected with a neutralizing antibody against IL‐6 (IL‐6 NA) or an IgG control 1 hour prior to exercise. The IL‐6 NA completely ablated exercised‐induced increases in hepatic pSTAT3, which occurred in parallel with an attenuated recovery of pAKTSer473, suggesting that IL‐6 contributes to exercise‐induced recovery of hepatic insulin action. Finally, to determine if IL‐6 directly regulates hepatocellular pAKTSer473, primary hepatocytes were isolated from lean mice and treated with free fatty acid (FFA: 250 μM oleate, 250 μM palmitate) for 24 hours as a means to increase lipid accumulation and insulin resistance. Cells were then treated with IL‐6 for 90 minutes, including insulin stimulation for the final 15 minutes. IL‐6 induced increases in pSTAT3 protein content were attenuated by FFA treatment. In addition, the FFA‐induced reduction in insulin‐stimulated pAKTSer473 was not rescued by IL‐6 treatment. Together, this data suggests that the recovery of hepatic insulin action after exercise in obese mice may involve an IL‐6 dependent mechanism; however, the effect of IL‐6 may not be directly in the hepatocytes.Support or Funding InformationThis work was partially supported by a NSERC grant (341158 to DCW) and a Veterans Affairs VHA‐CDA2 grant (IK2BX001299 to RSR).
Blunted Autonomic Response To Head Up Tilt In Individuals With Intellectual Disabilities: Preliminary Results
Authors: Hilgenkamp Thessa , Schroeder Elizabeth C. , White Daniel W. , Baynard Tracy , Fernhall Bo 
Published: November 2023

Individuals with intellectual disabilities (ID) have limited cardiorespiratory capacity, not explained by lack of motivation or lack of understanding the testing procedures. In individuals with ID who have Down syndrome, low cardiorespiratory capacity has been linked to autonomic dysfunction. Previous research suggests autonomic dysfunction may also be present in individuals with ID without Down syndrome but this has not been tested.PURPOSETo compare the autonomic response to head up tilt of individuals with ID to a control group without ID.METHODSThirteen individuals with ID and 12 individuals without ID were instrumented with an ECG‐lead and finger‐plethysmography for continuous heart rate and blood pressure recordings. After resting supine for 10 min, participants underwent 5 min head‐up tilt at 70 degrees with an electronic tilt table, followed by a 10 min supine recovery. The last five minutes of every position was used to calculate cardiovascular measures and time‐domain heart rate variability measures as non‐invasive indices of autonomic function.RESULTSIndividuals with ID showed different responses compared to individuals without ID for stroke volume, R‐R‐interval (RRI), root mean square of successive differences (RMSSD) and the proportion of times the change in consecutive intervals exceeds 50 milliseconds (pNN50) (p<0.05; Table).CONCLUSIONThese preliminary results suggest a blunted response to head‐up tilt in individuals with ID, but our findings need to be confirmed with a larger sample.Support or Funding InformationThe research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007–2013) under REA grant agreement n°625455.

Results in means (standard deviation). RRI=beat‐to‐beat interval, RMSSD= root mean square of successive differences, pNN50= the proportion of times the change in consecutive intervals exceeds 50 milliseconds

Baseline Supine
Head up tilt
Recovery Supine
Position × Group interaction effect

ID
Control
ID
Control
ID
Control
p‐value

Stroke volume
108 (28)
108 (23)
94 (35)
73 (14)
110 (30)
107 (23)
0.009**

Cardiac output
6.9 (1.5)
5.9 (1.1)
7.1 (2.1)
5.6 (0.8)
7.0 (1.5)
5.9 (1.2)
0.308

RRI mean
962 (111)
1098 (128)
808 (104)
772 (104)
972 (129)
1088 (124)
<0.001**

RMSSD
63 (24)
101 (46)
33 (16)
31 (16)
66 (30)
101 (49)
0.008**

pNN50
36 (17)
53 (16)
12 (12)
10 (11)
37 (19)
53 (19)
0.015*

p<0.05,
p<0.01
Pedometer‐determined physical activities of daily living can affect blood pressure regulation in healthy young adults after postural change
Authors: Yang Hongxia , Kotaki Yumika , Hoshi Junko , Bao Sarina , Tanno Hiromasa , Kanno Emi , Maruyama Ryoko 
Published: November 2023

BackgroundNumerous studies have examined the effects of physical activity (PA) on blood pressure (BP) or autonomic function through exercise interventions. However, few studies have used non‐intervention methods to observe the association between pedometer‐determined physical activities of daily living and BP and autonomic function in healthy young adults.ObjectiveThe purpose of this study was to examine whether the differences in pedometer‐determined physical activities of daily living cause the variation in BP and autonomic nerve activity in healthy young adults.MethodsFourteen Japanese healthy young adults aged 20–24 years participated in this study. A pedometer was used to measure the step count and to calculate other indexes of physical activity for 1 week. It was determined that 5 individuals comprised the high PA group (≥23 METs ■ hr/wk) and 9 individuals comprised the low PA group (<23 METs ■ hr/wk). Weight, height, BMI, muscle mass, body fat percentage, and basal metabolic rates were measured using a body composition analyzer. Then, we measured BP and heart rate variability at rest and during the postural change from the supine position to the sitting position. The ratio of low frequency (LF) components (0.04–0.15 Hz) to high frequency (HF) components (0.15–0.40 Hz) was used as an index of sympathetic nerve activity. HF was used as an index of parasympathetic nerve activity.ResultsThe high PA group exhibited significantly higher calorie consumption (P < 0.01) and fat combustion (P < 0.01). The mean diastolic blood pressure value in the sitting position (P < 0.02) for the high PA group was significantly higher than that of the low PA group. After a postural change from the supine position to the sitting position, although there were no significant changes in LF/HF and HF in both groups, systolic blood pressure (SBP) in the high PA group increased significantly (P < 0.05); however, the low PA group had a significant subsequent decrease in SBP after changing from the supine position to the sitting position (P < 0.01).ConclusionsThrough the measurement of pedometer‐determined physical activities of daily living in healthy adults, we concluded that individuals who performed more pedometer‐determined physical activities of daily living can maintain normal responses in blood pressure after a postural change, compared to individuals who performed fewer pedometer‐determined physical activities of daily living.Support or Funding InformationThis work was supported, in part, by a Grant‐in‐aid for Scientific Research (B) (25305018) from the Japan Society for the Promotion of Science.
Altered Hypoxia‐Induced Vascular Reactivity and Endothelial Repair Capacity in Hypertensive Men
Authors: Rocha Helena Naly Miguens , Garcia Vinicius Pacheco , Mattos João Dario , Rocha Marcos Paulo , Campos Monique Opuszcka , de Jesus Mansur Daniel Elias , da Nóbrega Antonio Claudio Lucas , Fernandes Igor Alexandre , Rocha Natália Galito 
Published: November 2023

IntroductionHypoxia induces peripheral vasodilation in healthy subjects, despite the occurrence of sympathoexcitation. Endothelial progenitor cells (EPC) mobilization from bone marrow and nitric oxide released by intact endothelium seem to exert important functions in the vasodilatory response to hypoxia. Even considering that both sympathetic overstimulation and endothelial dysfunction are major contributing factors to the pathophysiology of hypertension, it is still unknown whether those functions are preserved in patients with hypertension.AimTo determine the effects of hypoxia on sympathetic activity, peripheral blood flow, and endothelial biomarkers in patients with hypertension.MethodsSix normotensive men (NT; 44 ± 11 yrs, mean arterial pressure (MAP) 87 ± 6 mmHg) and seven non‐treated patients with hypertension (HT; 44 ± 10 yrs, MAP 110 ± 7 mmHg) were exposed to 5‐min bouts of: (1) Normoxia (21% O2) and (2) isocapnic‐Hypoxia (10% O2). Muscle sympathetic nerve activity [MSNA (microneurography; peroneal nerve)] recordings were obtained throughout the protocol, while femoral artery blood flow measurements (Doppler ultrasound) and blood samples were acquired during the last 30s of each condition. EPC (CD45dim/CD34+/VEGFR2+) and endothelial microparticles (EMP; CD42b‐/CD31+/AnnexinV+) were measured by flow cytometry, whereas nitrite concentration was determined by ozone‐chemiluminescence method.ResultsAt baseline, femoral arterial blood flow (HT 361.8 ± 262.6 ml.min−1 vs. NT 344.6 ± 75.5 ml.min−1), EMP (HT 12 ± 8 EMP/μL vs. NT 4 ± 1 EMP/μL) and nitrite (HT 0.35 ± 0.10 μM vs. NT 0.42 ± 0.12 μM) were similar between groups (p>0.05), while EPC were reduced in HT (35 ± 8 EPC/μL) compared to NT (86 ± 24 EPC/μL, p=0.02). During hypoxia, HT presented decreased femoral arterial blood flow (−110.2 ± 43.0 ml.min−1) and EPC (−7 ± 4 EPC/μL), while NT showed increased femoral arterial blood flow (+73.9 ± 37.4 ml.min−1, p=0.01) and EPC (98 ± 35 EPC/μL, p=0.01). MSNA increased only in HT (+12.7 ± 6.7 vs. NT +3.6 ± 1.6 bursts/min, p=0.01). There were no differences in nitrite (HT −0.01 ± 0.07 μM vs. NT 0.06 ± 0.09 μM) and EMP (HT 6.4 ± 16.1 EMP/μL vs. NT 3.5 ± 3.9 EMP/μL) between groups (p>0.05).ConclusionThese results suggest that patients with hypertension present diminished peripheral vascular reactivity in response to hypoxia, which could be associated with increased sympathetic activity observed in these individuals. Furthermore, EPC only increased in healthy subjects, suggesting an impaired endothelial repair capacity in patients with hypertension.Support or Funding InformationCNPq, FAPERJ, CAPES and FINEP.
Molecular Basis of Hypoxia Induced Excessive Erythrocytosis
Authors: Azad Priti , Haddad Gabriel 
Published: November 2023

ObjectiveSince polycythemia is a predominant trait in some high altitude dwellers (Chronic Mountain Sickness, CMS, or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human “experiment in nature” and studied both populations (with CMS and without, non‐CMS). Although polycythemia could be advantageous at high altitude because it increases O2‐carrying capacity, this adaptive pattern to high altitude has deleterious effects since blood increases its viscosity and induces serious morbidities, such as myocardial infarction and stroke in young adults.MethodsIn order to understand the molecular basis for polycythemia of high altitude, we generated a disease in‐the dish‐model by re‐programming fibroblasts from CMS and non‐CMS subjects. In the past, we have done whole genome sequencing of subjects from this region (CMS and non‐CMS) to study selective sweeps and genetic basis of CMS. In this study, by manipulating expression of some of these genes in using our in‐vitro model system, we are delineating the functional basis and the molecular mechanism(s) linked to the pathology.ResultsAs compared to sea level controls and non‐CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, CMS cells increased theirs remarkably (up to 60 fold) with a dose‐dependent response to graded hypoxia (1.5, 5, 10% O2). We knocked down SENP1 (a desumoylase) in CMS iPS cells using lentiviral constructs and observed a striking reduction (>90%) of the CMS excessive erythropoietic response to low O2. And, by over‐expressing SENP1 in non‐CMS iPS cells, the hypoxic response in these subjects increased enormously. By further analyzing RBC differentiation in hypoxia, we found that VEGF, GATA1 and Bcl‐xL increased their gene expression in the CMS erythroid cells, in contrast to their minimal expression in the other two populations. We demonstrate also that, by utilizing a SUMO‐GATA1 fused construct, GATA1 desumoylation, a target of SENP1, is critical for the CMS phenotype. Unlike GATA1, the over‐expression of the anti‐apoptotic gene Bcl‐xL (a GATA1 target), only partially rescued the blunted erythroid response to hypoxia in non‐CMS cells.ConclusionWe conclude that the increased erythropoietic sensitivity to hypoxia in CMS subjects is genetic in nature and depends on an increase in SENP1 expression and its desumoylation mediated activation of GATA1 under hypoxia. By combining the iPS technology with this unique Andean population that has adapted (or mal‐adaptated) to chronic hypoxia over thousands of years, we have built an important in‐vitro model. We believe that utility of this model lies not only for studying hypoxia‐induced polycythemia but also other hypoxia‐driven diseases experienced at sea level.Support or Funding InformationThis study is funded by National Institutes of Health (NIH) grants (1P01HL098053 and 5P01HD32573) to G.G. Haddad
Determinants of skeletal muscle work efficiency in patients with COPD
Authors: Layec Gwenael , Hart Corey R , Trinity Joel , Le Fur Yann , Jeong Eun‐Kee , Richardson Russell 
Published: November 2023

Skeletal muscle work inefficiency plays a major role in limiting exercise capacity in patients with chronic Obstructive Pulmonary Disease (COPD). However, the physiological mechanisms responsible for this excessive energy demand from the exercising muscle of patients with COPD remains poorly understood. To address this gap in our knowledge, we measured the cost of muscle contraction (ATP cost) in the quadriceps of patients with moderate to severe COPD (n=11) and age‐matched sedentary controls (n=12) with phosphorus magnetic resonance spectroscopy (31P‐MRS) during 1) maximal intermittent contractions to elicit a metabolic demand from both cross‐bridge cycling and ion pumping and 2) a continuous maximal contraction to predominantly tax cross‐bridge cycling. In addition, muscle fiber type distribution was determined in the vastus lateralis using immunofluorescence analysis. The ATP cost of contraction for both the continuous (Control: 0.11 ± 0.07 mM.min−1.N m−1; COPD: 0.12 ± 0.07 mM.min−1.N m−1) and intermittent (Control: 0.24 ± 0.17 mM.min−1.N m−1; COPD: 0.24 ± 0.18 mM.min−1.N m−1) protocols were not significantly different between groups with or without normalization for muscle mass (P>0.05). Somewhat surprisingly, fiber type distribution was also not different between groups (Type I; Control: 41 ± 12 %; COPD: 40 ± 18 %; Type II; Control: 59 ± 12 %; COPD: 60 ± 18 % respectively P>0.05). Of note, this finding of similar fiber type composition in controls and COPD was partly the consequence of a relatively high proportion of type II fibers in the elderly controls. These, somewhat serendipitous, data reveal that excessive energy demand from ion pumping or myosin ATPase per se is not an obligatory component of the skeletal muscle work inefficiency in COPD and suggest that the previously documented elevated ATP cost of contraction in the locomotor muscles of these patients was likely mediated by a fiber type shift. In practical terms, these findings highlight the potential importance of developing effective therapeutic strategies to limit the likely deleterious consequences of a skeletal muscle fiber type shift in the lower limbs of patients with COPD.Support or Funding InformationThis work was funded in part by grants from the Flight Attendant Medical Research Institute (FAMRI), NIH National Heart, Lung, and Blood Institute (PO1 HL 091830, K99HL125756) and VA Merit grant E6910R.
Myosin phosphorylation‐mediated potentiation does not alter the economy of work performed in fast skeletal muscles
Authors: Gittings William , Bunda Jordan , Vandenboom Rene 
Published: November 2023

The physiological role of myosin regulatory light chain (RLC) phosphorylation in fast skeletal muscle is unclear, as the resultant potentiation of contractile function comes with an undetermined energetic cost. We conducted in vitro experiments (25°C) to quantify contractile economy (i.e. energy cost/work performed) in potentiated extensor digitorum longus (EDL) muscles from wildtype and myosin light chain kinase knockout (skMLCK−/−) mice. Economy values were calculated as the ratio of total work performed to high‐energy phosphate consumption (HEPC) during a period of repeated isovelocity contractions that followed a potentiating stimulus (PS). The PS enhanced contractile parameters (concentric force and work) in both genotypes, although the effect was significantly greater in wildtype (1.38 ± 0.03 and 1.51 ± 0.03) vs. skMLCK−/− (1.10 ± 0.04 and 1.10 ± 0.05) muscles (P < 0.05, n = 8 for all data). During the experimental period of repetitive stimulation in the potentiated state, wildtype muscles performed ~58% more total work than skMLCK−/− muscles (94.05 ± 3.80 vs. 59.55 ± 4.10 J•kg−1; P < 0.001) without a statistical increase in HEPC (19.03 ± 3.37 vs. 16.02 ± 3.41 μmol~P; P = 0.27) or genotype difference in economy (5.74 ± 0.67 vs. 4.61 ± 0.71 J•kg−1μmol~P−1; P = 0.27). Importantly, when relative genotype differences were analyzed, the quantity of total work performed was ~3 fold greater than the increase in HEPC for wildtype muscles. Our results support the idea that myosin RLC phosphorylation‐mediated potentiation is a mechanism capable of augmenting sustained contractile function without significantly increasing energetic cost or decreasing economy.Support or Funding InformationNatural Sciences & Engineering Research Council of Canada (NSERC): Discovery Grant (R. Vandenboom)
Increased Superoxide Dismutase‐2 in skeletal muscle in a rat model of preterm birth
Authors: Hokanson Elise S , Tetri Laura , Braun Rudolf K , Eldridge Marlowe W 
Published: November 2023

BackgroundIn the United States an estimated 12% of births are preterm, meaning a significant number of infants are at increased risk for hypertension, type‐2 diabetes, and insulin resistance later in life. After a preterm birth, a common intervention used is oxygen therapy in order to improve oxygen delivery to systemic tissues. Although acutely life sustaining, there may be adverse effects of oxygen therapy in the long term. Many metabolic alterations have been identified in adults born preterm, including increased risk of insulin resistance and metabolic syndrome. In these conditions, there have been alterations in uncoupling protein‐3 (UCP‐3) expression, a protein that aids in the release of energy from the mitochondria as heat, and superoxide dismutase one and two (SOD‐1 and SOD‐2) expression, which metabolize reactive oxygen species. We hypothesized that altered levels of uncoupling protein and antioxidants would be observed at one year of age in a rat model of prematurity.MethodsWithin 12 hours of their birth, we exposed Harlan Sprague‐Dawley (SD) rat pups for 14 days to either normoxia (NORM, 21% oxygen, n=12, 6 males) or hyperoxia (HYP, 85% oxygen, n=12, 6 males) in custom chambers. After the 14 days, the pups were aged out to one year of age in standard room air. The gastrocnemius muscles were then harvested and flash frozen in liquid nitrogen. Western blotting was used to observe the differences in UCP3, SOD1, and SOD2. Statistics were run by two way ANOVA with Tukey's post hoc analysis.ResultsThere were no differences observed in UCP3 protein expression or SOD1 protein expression (p=0.8). There is a trend towards higher expression of SOD2 expression in HYP rats (p=0.9). There was a trend towards higher expression of SOD2 in the HYP rats compared to NORM rats (38% higher, p=0.08).ConclusionsNo difference in UCP3 expression is indicative that the main mechanism of uncoupling in the skeletal muscle is unaltered, at least in expression, in this rat model of prematurity. SOD1 is the form of SOD present in the cytoplasm, and indicates that there may not be an increased need for antioxidants in the cytoplasm. However, the potentially higher level of SOD2, the mitochondrial form, in HYP rats indicates that there may be increased need for antioxidants in the mitochondria. Previous data has shown altered mitochondrial mass and function in the HYP rats, and this observation of greater expression of SOD2, a potent antioxidant, further supports the possibility of altered mitochondrial function in the HYP rats.Support or Funding InformationNHLBI, R01 HL115061‐03, Suppl (Eldridge) & NHLBI, R01 HL115061 (Eldridge)