bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long QT syndrome type 3 caused by a PY‐motif mutation leading to altered ubiquitylation and increased expression of Nav1.5 in knock‐in mice
Authors: ROUGIER Jean-Sébastien , Albesa Maxime , Remme Carol Ann , Ogrodnik Jakob , Petitprez Séverine , Bankston John , Kass Robert S. , Bezzina Connie R. , Chung Wendy , Abriel Hugues 
Published: June 2021

BackgroundCongenital long QT syndrome type 3 (LQT3) is a cardiac arrhythmias caused by gain‐of‐function mutations in SCN5A, the gene encoding the sodium channel Nav1.5. This channel can be regulated via the ubiquitin ligase Nedd4‐2 which binds to the PY‐motif of Nav1.5.AimWe have investigated the mechanisms underlying the phenotype of a LQT3 family harboring a SCN5A mutation located in the PY‐motif (p.Y1981N) of Nav1.5.ResultsIn HEK cell, co‐immunoprecipitation experiments revealed that the interaction of Nav1.5 with Nedd4‐2 was abolished by the mutation. While the WT protein was ubiquitylated and the sodium current (INa) down‐regulated upon Nedd4‐2 co‐expression, no such regulation was observed with the mutant channel. In vivo relevance of this mechanism was assessed by generating a knock‐in (KI) mouse line bearing the p.Y1981N mutation. Ubiquitylation of the mutant channel expressed in KI hearts mice was reduced, and the total level of Nav1.5 protein was increased compared to WT littermates. INa and action potential duration were increased in KI cardiomyocytes compare to WT.ConclusionsThese results demonstrate a central role for Nav1.5 ubiquitylation in the regulation of sodium channel density in cardiomyocytes.Funding from the European Community's Seventh Framework Programme, EUTrigTreat, the Swiss National Science Foundation, and the Swiss Heart Foundation.
Impaired regeneration in ERRalpha deficient skeletal muscle
Authors: LaBarge Samuel , McDonald Marisa , Huss Janice 
Published: June 2021

The nuclear receptor transcription factor, Estrogen‐Related Receptor α (ERRα), regulates mitochondrial glucose and fatty acid oxidation and mitochondrial biogenesis in highly oxidative tissues. However, it is unknown whether ERRα is involved in adaptive skeletal muscle processes requiring metabolic remodeling like muscle regeneration. We employed skeletal muscle‐specific knockout mice (m‐ERRα−/−) to assess ERRα‐dependence of mitochondrial biogenesis and myofiber regeneration in tibialis anterior following cardiotoxin (CTX)‐induced injury. Expression of ERRα and its coactivator, PGC‐1α, were increased in regenerating WT myofibers, supporting their involvement in metabolic and contractile gene regulation during regeneration. Satellite cell (Pax7+) activation and macrophage (CD11b+) infiltration were the same in WT and m‐ERRα−/− injured muscles. In contrast, delayed regeneration in m‐ERRα−/− muscle was revealed by increased centralized nuclei at d15 and reduced myofiber area at d7 and d15 compared to WT mice. Mitochondrial enzyme activities (succinate dehydrogenase, cytochrome oxidase, citrate synthase) were not distinct early (d7) but were significantly lower in d15 m‐ERRα−/− regenerating fibers compared to WT. These results suggest that delayed early regeneration in m‐ERRα−/− muscles is not due to mitochondrial defects but may involve perturbed signaling of MAPK or calcineurin/CaMK pathways, that are modulated by ERRα and involved in muscle regeneration.(Support by NIH R01DK74700 (J.M.H.) and Morgan and Helen Chu graduate fellowship (S.L.)
Macrophage AMPKα1 is necessary for the resolution of inflammation during skeletal muscle regeneration
Authors: Mounier Rémi , Theret Marine , Cuvellier Sylvain , Sakamoto Kei , Zibrova Darya , Foretz Marc , Viollet Benoit , Chazaud Bénedicte 
Published: June 2021

Adult skeletal muscle has the unique capacity to regenerate. Muscle regeneration is always associated with inflammation and notably macrophages (MPs), which play dual role. Soon after injury, inflammatory monocyte‐derived macrophages (M1 phenotype) stimulate myogenic cell proliferation. After phagocytosis of muscle debris, MPs switch their phenotype to acquire an anti‐inflammatory profile (M2) and stimulate myogenic cell differentiation and myofibre growth. Here, we explored the role of AMPK in the resolution of inflammation during muscle repair.AMPKα1 KO muscle shows both a delay and an impairment of post‐injury regeneration. These deficiencies are also observed in LysM‐CRE;AMPKfl/fl muscle, confirming the MP specificity of AMPK requirement. In vitro, AMPKα1 KO MPs hardly acquire a M2 profile upon cytokine stimulation. Their phagocytic activity is also altered. In vivo analysis of MP subpopulations (using the AMPKα1−/−;CX3CR1GFP/+ mouse) during muscle repair shows that the number of intramuscular MPs exhibiting the M2 phenotype is reduced in the AMPKα1 KO compared to the WT mouse. Accordingly, leukocytes from AMPKα1 KO muscle do not increase their expression of markers associated with the resolution of inflammation during muscle regeneration.These results strongly support that AMPKα1 is one key regulator of MP switch at time of resolution of inflammation and is essential for a proper muscle repair.
Hypercapnia does not improve hyperthermic simulated hemorrhagic tolerance
Authors: Lucas Rebekah A.I. , Pearson James , Ganio Matthew S. , Crandall Craig G. 
Published: June 2021

This study tested the hypothesis that hypercapnia induced increases in cerebral perfusion improves tolerance to a simulated hemorrhagic challenge in heat stressed individuals. Seven individuals (32±9 y; 73±15 kg) underwent passive heat stress followed by a hemorrhagic challenge on two separate days (randomized). Hemorrhage was simulated via progressive lower body negative pressure (LBNP) to pre‐syncope after body core (intestinal) temperature was raised ~1.5 °C using a water perfused suit. From 30 Torr LBNP to pre‐syncope, subjects inhaled either (blinded) a hypercapnic gas mixture (5% carbon dioxide [CO2], 21% oxygen, balance nitrogen) or normal room air (SHAM). Middle cerebral artery blood velocity (MCAv, transcranial Doppler) and end tidal CO2 (PETCO2, capnograph) were measured. 5% CO2 increased PETCO2 at 30 Torr LBNP (15±3 mmHg) and pre‐syncope (19±3 mmHg), compared to SHAM (P<0.01). Subsequently, MCAv was higher in the 5% CO2 trial at 30 Torr (24±10 cm.s−1, ~33%) and presyncope (21±14 cm.s−1, ~30%) relative to the SHAM (P<0.01). However, hypercapnia did not alter LBNP tolerance time (5% CO2: 7.5±3.5 min; SHAM: 9.1±3.6 min; P=0.33). These data indicate that inhaling a hypercapnic gas mix and circumventing hyperventilatory‐induced hypocapnia does not improve an individualˈs tolerance to a hyperthermic hemorrhagic challenge, despite improving cerebral perfusion.Supported by NIH Grant HL061388
Sudomotor activity and heat balance with serial cooling and heating of thermosensors in the esophagus and stomach
Authors: Jay Ollie , Bain Anthony R , Lesperance Nicole C 
Published: June 2021

This study assessed heat balance parameters and characterized transient sweating responses on the forehead following graded changes in local temperature of the esophagus and stomach from ingesting water of different temperatures. Seven male participants cycled for 75‐min in a temperate environment while ingesting four 3.2 mL·kg−1 boluses of either 1.5°C, 10°C, 37°C or 50°C water, 5‐min before, and 15, 30 and 45‐min after the start of exercise at 50% VO2max. Whole‐body sweat loss (WBSL), rectal temperature (Tre), mean skin temperature (Tsk) and local sweat rate on the forehead (SRhead) were measured throughout. Evaporative heat loss from sweating (Esk), respiratory heat loss, dry heat losses and heat exchange with ingested water were subsequently calculated to estimate net body heat storage (S). Despite no differences in Tre or Tsk, the onset time for sudmotor activity on the forehead was significantly greater with declining fluid temperature (P<0.05), and both mean SRhead throughout exercise and WBSL was significantly lower with 1.5°C compared to 50°C water ingestion (P=0.002). Values for S were significantly greater following 1.5°C water ingestion relative to 50°C (P=0.033), indicating a disproportionate reduction of thermoregulatory sweating, and therefore Esk, relative to the internal heat transfer with 1.5°C water. It is proposed that these data present evidence of independent thermoafferent processes arising from changes in local temperature of the esophagus and/or stomach.Funding for the study was provided by a NSERC discovery grant.
Activation of hemostatic pathways by exercise induced hyperthermia
Authors: Hopman Maria , Eijsvogels Thijs , Veltmeijer Matthijs , van Geffen Mark , Thijssen Dick , van Heerde Waander 
Published: June 2021

BACKGROUNDRetrospective studies indicated that patients with heat stroke have a sustained activation of coagulation, fibrinolysis and platelets. However, little is known about changes in haemostatic parameters in hyperthermic athletes without exertional heat stroke. Therefore, the aim of this study was to determine changes in thrombin and plasmin generation after exercise induced hyperthermia.METHODSCore body temperature was measured before and at the finish line of a 15 km run (n=16, 51±8 years). Venous blood samples were collected pre‐ and post‐race. The Novel Haemostasis Assay was used to measure thrombin and plasmin generation simultaneously. This allows insight in the interaction between coagulation and fibrinolysis.RESULTSCore body temperature increased from 37.7±0.5°C to 39.4±0.9°C. The time to thrombin peak decreased from 9.2±2.3 min to 8.1±1.0 min (p<0.05), while the thrombin peakheight increased from 178±63 nM to 190±67 nM (p<0.001). The plasmin peak‐time increased from 28.4±9.5 min to 32.3±10.9 min (p<0.05), with a decrease in plasmin peakheight from 4.3±4.0 nM to 2.7±2.1 nM (p=0.07).CONCLUSIONAn increase of 1.7°C in core body temperature stimulated coagulation by enhancing thrombin generation and reducing plasmin generation. These innovative results suggest that exercise induced hyperthermia leads to activation of the coagulation pathway.
Leucine preserves muscle and strength and enhances recovery following bed rest
Authors: English Kirk L. , Mettler Joni , Mamerow Madonna M. , Mathers Charles H. , Pattarini James M. , Paddon-Jones Douglas 
Published: June 2021

Reduced mechanical loading is a hallmark of hospitalization and space flight, and contributes to a rapid decrease in muscle mass and functional performance. Mechanistically, these changes are mediated by a 30% reduction in the anabolic response to regular meals. If the ability to exercise is compromised, nutritional interventions represent one of the few viable alternatives. To this end, we added leucine (0.06 g · kg lean mass · meal−1; LEU) to the meals (containing 0.9 g protein · kg · day−1) served to adults (45–60 y) during 14 d bed rest. Our goal was to reduce the loss of muscle mass and function and facilitate recovery during 7 d of rehabilitation. During bed rest, control subjects (CON) lost 3‐ times more total lean body mass than LEU (CON: −3021 ± 400 g vs. LEU: −966 ± 264 g; p=0.001). Following rehabilitation, lean mass deficits persisted in CON while LEU returned to near pre‐bed rest values (CON: −1746 ± 303 g; LEU: −140 ± 367 g). The loss of isometric knee extensor peak torque was also three times greater in CON (−20.3 ± 6.8%) vs. LEU (−7.0 ± 2.5%; p=0.07). Changes in knee extensor total work during a 20 repetition isokinetic endurance test at 180° · s−1 followed a similar pattern (CON: −18.0 ± 7.4% vs. LEU: −5.3 ± 2.8%; p=0.08). These preliminary findings indicate that supplementing regular meals with a small amount of leucine attenuates the loss of muscle mass and function typically associated with bed rest and facilitates recovery.Grant Funding Source : NSBRI
Gene Expression Changes After a Single Botox Injection in the Rat Tibialis Anterior Muscle
Authors: Mathewson Margie , Minamoto Viviane , Subramaniam Shankar , Ward Samuel , Lieber Richard 
Published: June 2021

Here we report the time course of gene expression changes after a single injection of botulinum toxin type A (Botox®, Allergan, Inc., Irvine, CA). Following an approved Institutional Animal Care and Use Committee protocol, 90 male 3‐month‐old Sprague‐Dawley rats were given a single 100 μL saline injection containing either 6U/kg Botox® or saline only (control) in their right tibialis anterior (TA) muscle. TAs from four Botox® rats each were collected at: 1 week, 1 month, 3 months, and 1 year after injection, as well as 4 control TAs at 3 months. Gene expression was measured in 20 animals using Affymetrics rat 230 2.0 chips. Gene significance and fold change were determined with Genespring software. Muscle function was measured in 8 animals per time point. The number of genes differing significantly in expression from the control decreased at each time point: 1 week – 2887, 1 month – 481, 3 months – 46, and 1 year – 17 genes. After 1 week, the main significant changes occurred in genes of metabolism and the neuromuscular junction. Many major metabolic pathways were down regulated. At intermediate time points, genes involved in differentiation and repair were up regulated. These results demonstrate that transcriptional changes in muscle occur on a relatively rapid time scale, resolving within 3 months, but muscle functional deficits were shown to persist for up to a year.This work was funded by Allergan, Inc. and NIH grant HD50837.
Antioxidant treatment during development prevents low birth weight, hypertension, and enhanced sensitivity to mild renal ischemia in offspring exposed to placental insufficiency
Authors: Ojeda Norma Beatriz , Wilkening Steven , Dasinger John , Alexander Barbara T , Graves Glen , Rhodes Phil 
Published: June 2021

Placental insufficiency results in offspring with low birth weight (LBW), hypertension, and enhanced susceptibility to mild renal ischemia associated with increased oxidative stress. This study investigated whether early antioxidant treatment would prevent programming of cardio‐renal disease. The antioxidant tempol (1mMol/L by drinking water) was administered from E14 to P21 to dams exposed to placental insufficiency (LBW offspring) or a sham procedure (normal birth weight, or NBW offspring). Blood pressure and renal function following mild renal ischemia were assessed in offspring at 6 months of age. In offspring exposed to placental insufficiency, early antioxidant treatment prevented the development of low birth weight, hypertension, and enhanced renal dysfunction following mild renal ischemia. Thus, these findings indicate that early intervention may prevent the developmental origins of cardio‐renal disease. Supported by HL074927 and HL51971

NBW
LBW
NBW + Tempol
LBW + Tempol

Birth weight (g)
6.62±0.39
5.15±0.04*
7.08±0.07
7.19±0.24†

Mean arterial pressure (mmHg)
137±1.20
161±0.80*
133±2.50
133±2.00†

Glomerular Filtration Rate (ml/min/g/kidney)
1.21±0.13
0.22±0.01*
1.07±0.15
0.97±0.02†

Renal vascular resistance (mmHg/ml/min)
7.49±0.33
37.07±1.93*
8.27±0.89
8.48±0.96†

Effective renal plasma flow (ml/min)
9.13±0.04
2.43±0.02*
8.94±0.24
9.16±1.03†

P<0.05 vs. NBW
P<0.05 vs. L BW
Estradiol prevents increased cortical AQP2 expression and urine osmolality in rats subjected to ovariectomy for 7 days
Authors: Norregaard Rikke , Wang Yan , Miller-Little William , Frøkiær Jørgen 
Published: June 2021

Female sex hormones are suggested to be involved in the regulation of renal water handling. We hypothesized that changed in renal water handling in response ovariectomy (OVX) is associated with dysregulation of renal AQP2 and can be improved with estradiol or progesterone treatment.Rats were subjected to OVX for 7 and 14 days and treated with estradiol (25 μg/kg/day) or progesterone (10 mg/kg/day) and the expression of AQP2 were examined in the inner medulla (IM) or cortex by semiquantitative immunoblotting.Ovariectomy is associated with decreased serum estradiol and progesterone levels. Rat subjected to 7 and 14 days OVX had increased bodyweight (BW) and food intake which was normalized by estradiol treatment, whereas progesterone had no effect. Decreased urine output and increased urine osmolality after 2 and 7 days OVX were prevented by both estradiol and progesterone treatment. There was no change after 14dOVX. AQP2 and phospho‐Ser256‐AQP2 (pAQP2) protein level were increased in cortex from OVX rats at day 7 and this was prevented by estradiol administration whereas progesterone did not change AQP2. No change in AQP2 and pAQP2 were observed after 14dOVX.In conclusion, estradiol prevents dysregulation of cortical AQP2 and increased urine concentration in rats subjected to OVX for 7 days.
Hepatic foxO1 acetylation is regulated by menin and influenced by insulin signaling
Authors: Wuescher Leah , Angevine Kristine , Mensah-Osman Edith 
Published: June 2021

ObjectiveTo elucidate the relationship between hepatic menin and FoxO1 with respect to protein interaction and post‐translational modification of a metabolically relevant protein.MethodNIH‐3T3 cells were stably transfected with human insulin receptor, serum starved, and protein levels were measured. HepG2 cells were serum starved and treated with 100nM insulin. Animals were fasted 18h, re‐fed 4h, 7h, and random fed.ResultsMenin levels were significantly decreased by 24h exposure to insulin in 3T3 cells stably transfected with the human insulin receptor, however acute effects of insulin show increases in menin mRNA expression. In the liver and HepG2 cells menin interacts with the metabolic protein FoxO1 in an insulin dependent manner. Menin siRNA results in an insulin dependent decrease in FoxO1 acetylation.ConclusionsInsulin regulates menin expression both acutely and chronically in a biphasic manner. Furthermore, insulin mediates FoxO1 and menin interaction after 2h of exposure in HepG2 cells and with fasting and refeeding in C57/BLK6 mice. Loss of menin expression down‐regulate the acetylation state of FoxO1 in an insulin dependent manner. This data implicates menin in the regulation of a metabolic pathway via post‐translational modification of FoxO1 which regulates its cellular localization.Institutional Funding from the University of Toledo College of Medicine was used for these studies.
The N‐terminal loop of endothelin: 2 sites to a story
Authors: Compeer Matthijs G , Suylen Dennis PL , Hackeng Tilman M , De Mey Jo GR 
Published: June 2021

Endothelin‐1 (ET‐1) and (Trp6Leu7)Endothelin‐1 (ET‐2) are endogenous endothelinA (ETA)‐receptor agonists with comparable affinity and efficacy. However, the different amino acids on position 6 and 7 suggest differences in pharmacology.We used wire myography to investigate ETA‐receptor mediated arterial contractions in a setting minimizing effects of the endothelium and of sensory‐motor nerves. Using ET‐1, ET‐2, the novel chimeras Trp6ET‐1 and Leu7ET‐1 and the selective ETA‐receptor antagonist BQ123, we investigated the role of amino acids on position 6 and 7.We found that Leu7ET‐1 had a 30‐fold reduced contractile potency, compared to ET‐1. Trp6ET‐1 showed no apparent affinity at up to 256 nM. The antagonist affinity of BQ123 depended on the ETA‐agonist used (pKB: Leu7ET‐1 > ET‐1 > ET‐2). The extent of antagonist‐induced relaxations of ET‐precontracted arteries also depended on the agonist used. Furthermore the preventive effects of the antagonist differed from its relaxing effects.Our results indicate roles of agonist N‐terminal loop amino acids in allosteric modulation of ETA‐receptor function. When treating ET‐related diseases, taking into account which isoform is involved might improve treatment outcome.This study was performed within the framework of TI Pharma project T2‐301.
Effects of Exercise Training on NASH‐Induced Oxidative Stress in Heart of Rats
Authors: Huang Wei-Chih , Chan Che-Chang , Hung Shan-Ken , Yang Ai-Lun , Tsai Shiow-Chwen 
Published: June 2021

Methionine‐choline‐deficient (MCD) diet will develop Non‐alcoholic steatohepatitis (NASH) is characterized, is similar to the histopathologic changes that occur in NASH in humans. The influence of NASH on heart is still unclear.PURPOSETo investigate the interaction of exercise training and MCD diet on oxidative stress in heart.METHODSAdult male Sprague Dawley rats were randomly divided into 5 groups: control (fed normal diet, W0), MCD diet fed for 9 weeks or 14 weeks combined without (W9, W14) or with exercise training (W9+Ex, W14+Ex). The exercise training was treated for 4 weeks before sacrifice. The AST level in plasma and the antioxidation activity of liver tissue were assay by commercial kit. The statistical analysis was done using the one‐way ANOVA for independent samples.RESULTSMCD diet showed a rapid induction of AST and hepatic steatosis, loss of body weight and heart weight. The lipid peroxidation levels of W14 and W14+Ex were increased. Cpmpared wth W0, The activity of SOD were significantly increased in W14 (p<0.0001) and in W14+Ex (p=0.012). Compared with W14, W14+Ex decrease the activity of SOD, but increase the activity of catalase. The increased production of GSH and GSSG in W9 were due to the increased activity of GPx and GR.CONCLUSIONExercise training enhanced the activity of catalase and decreased the production of lipid peroxidation in LV.
Reduced detrusor contractility in cavin‐1 deficient mice
Authors: Sadegh Mardjaneh Karbalaei , Uvelius Bengt , Ekman Mari , Swärd Karl , Rippe Catarina 
Published: June 2021

ObjectiveCaveolae are omega‐shaped membrane microdomains which are abundantly expressed in the detrusor and has been shown to be of great importance for bladder function. Biogenesis of caveolae is dependent on caveolin‐1, membrane cholesterol and the recently discovered cavin‐1 protein. The aim of this study was to investigate detrusor contractility and function in cavin‐1 knockout (KO) mice.MethodsElectron microscopy was used to visualize caveolae. Detrusor nerves were activated using electrical field stimulation (EFS).Results and conclusionExamination of ultrastructure confirmed the absence of caveolae in the KO mice. In response to high potassium as well as to EFS the cavin‐1 deficient mice displayed decreased force of contraction. In addition, EFS (in the presence of a muscarinic antagonist) revealed a reduced cholinergic component in the KO detrusor. Bladder to body weight was significantly increased in the KO mice suggesting bladder hypertrophy. We suggest that cavin‐1 deficiency results in impaired detrusor contractility and reduced cholinergic signalling that in turn might induce bladder hypertrophy. Supported by Swedish Research Council and the Crafoord foundation.
Mathematical Model of Mixed Venous SO2 Transients at Onset of Exercise in Discrete Capillary Networks
Authors: Fraser Graham Mathew , Goldman Dan , Kowalchuk John , Ellis Christopher G 
Published: June 2021

Increases in muscle O2 consumption (VO2) result in higher blood flow to accommodate changing metabolic demand. The time required for diffusion of O2 within a muscle volume to support increased VO2 causes tissue PO2 and mixed venous SO2 to lag behind VO2. The purpose of this study was to determine how diffusive transport affects time transients in venous SO2 following increases in blood flow and VO2. A finite difference model was used to simulate O2 transport in a discrete 3D microvascular network mapped from rat skeletal muscle using intravital video microscopy. Measurements were made in vivo to determine baseline simulation parameters for red blood cell supply rate (RBC SR), capillary inlet SO2, and VO2. Using the baseline solution as a starting point, exercise was simulated using simultaneous 6X step increases in VO2 and RBC SR. Tissue PO2 and capillary venous outflow SO2 (cvSO2) were recorded at 0.2s intervals until steady‐state (SS) was reached. SS mean tissue PO2 decreased from 37.2 ± 2.7 at baseline to 18.2 ± 5.9 mmHg in simulated exercise. Figure I shows the cvSO2 profile of blood as it exits the volume and the relative time course of the step change. This model demonstrates that despite instantaneous step increases in muscle VO2 and microvascular blood flow, diffusive transport of O2 in skeletal muscle imposes an observable time transient to cvSO2 following the onset of exercise.Supported by CIHR MOP 102504 & NIH HL089125