We recently reported that the nonselective cyclooxygenase (COX) inhibitor ketorolac attenuated sweating but not cutaneous vasodilation during moderate-intensity exercise in the heat. However, the specific contributions of COX-1 and COX-2 to the sweating response remained to be determined.

We tested the hypothesis that COX-1 but not COX-2 contributes to sweating with no role for either COX isoform in cutaneous vasodilation during moderate-intensity exercise in the heat.

In thirteen young males (22 ± 2 years), sweat rate and cutaneous vascular conductance were measured at three forearm skin sites that were continuously treated with (1) lactated Ringer's solution (Control), (2) 150 mmol·L-1 celecoxib, a selective COX-2 inhibitor, or (3) 10 mmol L-1 ketorolac, a nonselective COX inhibitor The Journal of Physiology publishes original Research Papers in all areas of are particularly keen to publish papers that have a clinical or translational focus, .

Participants first rested in a non heat stress condition (≥85 min, 25°C) followed by a further 70-min rest period in the heat (35°C). They then performed 50 min of moderate-intensity cycling (~55% peak oxygen uptake) followed by a 30-min recovery period.

At the end of exercise, sweat rate was lower at the 150 mol·L-1 celecoxib (1. 30 mg·min-1 ·cm-2 ) treated skin sites relative to the Control site (1. Additionally, sweat rate at the ketorolac site was attenuated relative to the celecoxib site (P ≤ 0. Neither celecoxib nor ketorolac influenced cutaneous vascular conductance throughout the experiment (both P >0. We showed that both COX-1 and COX-2 contribute to sweating but not cutaneous vasodilation during moderate-intensity exercise in the heat in young men. Glucagon is the body's main hyperglycemic hormone, and its secretion is dysregulated in type 2 diabetes mellitus (T2DM).

The incretin hormone glucagon‐like peptide‐1 (GLP‐1) is released from the gut and is used in T2DM therapy. Uniquely, it both stimulates insulin and inhibits glucagon secretion and thereby lowers plasma glucose levels.

In this study, we have investigated the action of GLP‐1 on glucagon release from human pancreatic islets. 5% of the ‐cells possess detectable GLP‐1R immunoreactivity. Despite this, GLP‐1 inhibited glucagon secretion by 50–70%.

This was due to a direct effect on ‐cells, rather than paracrine signaling, because the inhibition was not reversed by the insulin receptor antagonist S961 or the somatostatin receptor‐2 antagonist CYN154806. The inhibitory effect of GLP‐1 on glucagon secretion was prevented by the PKA‐inhibitor Rp‐cAMPS and mimicked by the adenylate cyclase activator forskolin.

Electrophysiological measurements revealed that GLP‐1 decreased action potential height and depolarized interspike membrane potential. Mathematical modeling suggests both effects could result from inhibition of P/Q‐type Ca2+ channels.

In agreement with this, GLP‐1 and ‐agatoxin (a blocker of P/Q‐type channels) inhibited glucagon secretion in islets depolarized by 70 mmol/L K+ o, and these effects were not additive. Intracellular application of cAMP inhibited depolarization‐evoked exocytosis in individual ‐cells by a PKA‐dependent (Rp‐cAMPS‐sensitive) mechanism.

We propose that inhibition of glucagon secretion by GLP‐1 involves activation of the few GLP‐1 receptors present in the ‐cell membrane. The resulting small elevation of cAMP leads to PKA‐dependent inhibition of P/Q‐type Ca2+ channels and suppression of glucagon exocytosis.

GLP‐1 suppresses glucagon secretion in human pancreatic alpha‐cells by inhibition of P/Q‐type Ca2+ channelsAbdominal aortic aneurysm (AAA) is a progressive disease that has an increasing prevalence with aging, but no effective pharmacological therapy to attenuate AAA progression is currently available. We reported that the prostaglandin E receptor EP4 plays roles in AAA progression.

Here, we show the effect of CJ-42794, a selective EP4 antagonist, on AAA using two mouse models (angiotensin II- and CaCl2 -induced AAAs) and human aortic smooth muscle cells isolated from AAA tissue. 2 mg/kg per day) for 4 weeks significantly decreased AAA formation in ApoE-/- mice infused with angiotensin II (1 g/kg per min), in which elastic fiber degradation and activations of matrix metalloproteinase (MMP)-2 and MMP-9 were attenuated. Interleukin-6 (IL-6) proteins were highly expressed in the medial layer of angiotensin II-induced mouse AAA tissues, whereas this expression was significantly decreased in mice treated with CJ-42794.

AAA formation induced by periaortic CaCl2 application in wild-type mice was also reduced by oral administration of CJ-42794 for 4 weeks. After oral administration of CJ-42794 beginning 2 weeks after periaortic CaCl2 application and continuing for an additional 4 weeks, the aortic diameter and elastic fiber degradation grade were significantly smaller in CJ-42794-treated mice than in untreated mice.

Additionally, in smooth muscle cells isolated from human AAA tissues, stimulation of CJ-42794 inhibited PGE2 -induced IL-6 secretion in a dose-dependent manner and decreased PGE2 -induced MMP-2 activity. These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression.

A long-term goal in renal physiology is to understand the mechanisms involved in collecting duct function and regulation at a cellular and molecular level. The first step in modeling of these mechanisms, which can provide a guide to experimentation, is the generation of a list of model components.

We have curated a list of proteins expressed in the rat renal inner medullary collecting duct (IMCD) from proteomic data from 18 different publications. The database has been posted as a public resource at https:// /ESBL/Database/IMCD Proteome Database/.

To search the IMCD Proteomic Database efficiently, we have created a Java-based program called curated database Basic Local Alignment Search Tool (cdbBLAST), which uses the NCBI BLAST kernel to search for specific amino acid sequences corresponding to proteins in the database.

cdbBLAST reports information on the matched protein and identifies proteins in the database that have similar sequences. We have also adapted cdbBLAST to interrogate our previously published IMCD Transcriptome Database.

We have made the cdbBLAST program available for use either as a web application or a downloadable . Database searching based on protein sequence removes ambiguities arising from the standard search method based on official gene symbols and allows the user efficient identification of related proteins that may fulfill the same functional roles. Acute ischemic cardiogenic shock is associated with poor prognosis, and the impact of inotropic support on diastolic function in this context is unclear.

We assessed two suggested new inotropic strategies in a clinically relevant pig model of ischemic acute heart failure (AHF): treatment with the myosin activator omecamtiv mecarbil (OM) or dobutamine and ivabradine (D+I). Left ventricular (LV) ischemia was induced in anesthetized pigs by coronary microembolization (n = 12).

5 mg/kg per h) (n = 6) or D+I (5 g/kg per min + 0. Ischemia reduced the stroke volume (SV), despite the increased left atrial pressure associated with impaired LV early relaxation, systolic dilatation, and LV late diastolic stiffness.

Both treatments improved systolic ejection, but only D+I increased the SV from 26 ± 5 to 33 ± 5 mL. D+I enhanced LV early relaxation (Tau; from 45 ± 11 to 29 ± 4 msec) and prolonged the diastolic time (DT) from 338 ± 60 to 352 ± 40 msec.

In contrast, OM prolonged Tau (42 ± 5 to 62 ± 10 msec) and shortened the DT (from 326 ± 68 to 248 ± 84 msec). Our data suggest that enhanced early relaxation by D+I improves LV pump function in postischemic acute heart failure.

In contrast, OM worsened lusitropy in this model. Graphical illustration of typical left ventricular pressure volume loop from ischemic pig hearts treated with dobutamine combined with ivabradine (D+I) or omecamtiv mecarbil (OM).

As seen D+I improved post ischemic function by increased ejection at preserved diastolic function. In contrast, OM induced a diastolic constrain that hamper the therapeutic potential of the drug in ischemic acute heart failure.

The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss- and gain-of-function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (IhERG ) exhibits uniquely fast inactivation involving conformational changes to the channel pore.

The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on IhERG profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C.

Under conventional voltage clamp, the current-voltage (I-V) relation for IhERG exhibited a marked right-ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented IhERG , which also peaked much earlier during the AP plateau than did wild-type (WT) IhERG .

Instantaneous I-V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance-voltage relation showed an earlier and more sustained rise in S631A compared to WT IhERG conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted IhERG in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions.

Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 mol/L) against S631A IhERG . Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.

Dietary apple polyphenols (AP) have been shown to exhibit beneficial effects on muscle endurance. Fast‐to‐slow change in the composition of myosin heavy chains was known as one of the molecular mechanisms.

Here, we examined the effects of dietary AP on the capillaries and mitochondria in the rat skeletal muscle to elucidate the mechanisms underlying muscular endurance enhancement. Twenty‐four Wistar male rats were divided into three groups, namely, the control group, 0.

5% AP group, and 5% AP group (n = 8 in each group). After a feeding period of 4 weeks, rats were dissected, gastrocnemius muscles were removed, and the density of capillaries and levels of mitochondrial proteins were analyzed.

Capillary density of the gastrocnemius increased to 17. 8% in rats fed with 5% AP as compared to the control rats.

No significant change was observed in the mitochondrial content and dynamics (fusion/fission) of regulatory proteins. To investigate the mechanisms underlying the increase in the capillary density, positive (vascular endothelial cell growth factor, VEGF) and negative (thrombosponsin‐1, TSP‐1) factors of angiogenesis were analyzed.

TSP‐1 expression significantly decreased in rats fed with 0. 5% AP and 5% AP by approximately 25% and 40%, respectively, as compared with the control rats.

There were no significant differences in VEGF expression. Thus, dietary AP may increase the muscle capillary density by decreasing TSP‐1 expression.

We concluded that the increase in the capillary density and the fast‐to‐slow change in myosin heavy chains by AP feeding are the main causes for muscle endurance enhancement in Wistar rats. In this study, we examined the effects of dietary apple polyphenols on the capillaries in the rat skeletal muscle to elucidate the mechanisms underlying muscular endurance enhancement.

Dietary apple polyphenols increase the muscle capillary density by decreasing TSP‐1 expression. Consumption of a representative fast‐food meal (FFMeal) acutely impairs peripheral conduit artery vascular function; however, the effect on cerebral vascular function remains unknown.

This study tested the hypothesis that a FFMeal would impair cerebral vascular function as indexed by an attenuated increase in cerebral vascular conductance (CVCI) in the middle cerebral artery (MCA) during a hypercapnic challenge. 8 kg/m2) were studied under two conditions; a standardized FFMeal (990 kcals, 50% fat, 36% carbohydrate, 14% protein, and 2120 mg sodium) and a fasting control condition.

Basal hemodynamics, cerebral vasomotor reactivity (CVMR), and brachial artery flow‐mediated dilation (BA FMD) were completed after an overnight fast (Pre) and again 2 h and 4 h later both days. To assess CVMR, subjects rebreathed from a 5‐L bag while MCA velocity (MCAVmean) was measured using transcranial Doppler (TCD) ultrasound and converted into CVCI (MCAVmean/mean arterial pressure).

Peripheral artery endothelial function was assessed via BA FMD following a standard 5‐min occlusion protocol. However, despite significant impairment in BA FMD, neither peak CVCI%baseline nor CVMR was affected by the FFMeal (Control–Pre: 1. These results suggest that cerebral vascular reactivity to hypercapnia in healthy young men is not altered by an acute FFMeal.

It is well known that a common fast‐food meal impairs peripheral artery endothelial function. However, its effect on cerebral vascular function remains relatively unknown.

The present findings confirm previous literature of an impaired peripheral artery function following a high‐fat meal; however, there was no effect of the meal on cerebral vascular function. After exposure to microgravity, or head-down bed rest (HDBR), fluid loading is often used with the intent of increasing plasma volume and maintaining mean arterial pressure during orthostatic stress.

Nine men (aged 18-32 years) underwent three randomized trials with lower body negative pressure (LBNP) before and after: (1) 4-h of sitting with fluid loading (1 g sodium chloride/125 mL of water starting 2. 5-h before LBNP), (2) 28-h of 6-degree HDBR without fluid loading, and (3) 28-h of 6-degree HDBR with fluid loading.

After 28-h HDBR, fluid loading did not protect against the loss of plasma volume (-280 ± 64 mL without fluid loading, -207 ± 86 with fluid loading, P = 0.

472) nor did it protect against a drop of mean arterial pressure (P = 0. 017) during LBNP (Post-28 h HDBR response from 0 to -40 mmHg LBNP: 88 ± 4 to 85 ± 4 mmHg without fluid loading and 93 ± 4 to 88 ± 5 mmHg with fluid loading, P = 0.

However, fluid loading did protect against the loss of stroke volume index and central venous pressure observed after 28-h HDBR.

Fluid loading also attenuated the increase of angiotensin II seen after 28-h HDBR and throughout the LBNP protocol (Post-28 h HDBR response from 0 to -40 mmHg LBNP: 16. Our results indicate that fluid loading did not protect against plasma volume loss due to HDBR or change blood pressure responses to LBNP. However, changes in central venous pressure, stroke volume and fluid regulatory hormones could potentially influence longer duration studies and those with more severe orthostatic stress.

Although low pressure baroreflex (LPB) has been shown to elicit various cardiovascular responses, its impact on sympathetic nerve activity (SNA) and arterial baroreflex (ABR) function has not been fully elucidated. The aim of this study was to clarify how volume loading‐induced acute LPB activation impacts on SNA and ABR function in normal rats.

In 20 anesthetized Sprague‐Dawley rats, we isolated bilateral carotid sinuses, controlled carotid sinus pressure (CSP), and measured central venous pressure (CVP), splanchnic SNA, and arterial pressure (AP). We infused blood stepwise (3 mL/kg/step) to activate volume loading‐induced LPB.

Under the ABR open‐loop condition, stepwise volume loading markedly increased SNA by 76. In contrast, further volume loading suppressed SNA toward the baseline condition.

Bilateral vagotomy totally abolished the changes in SNA by volume loading. To assess the impact of LPB on ABR function, we changed CSP stepwise.

4 mmHg) significantly shifted the sigmoidal CSP–SNA relationship (central arc) upward from baseline, whereas high volume loading (CVP = 5. Volume loading shifted the linear SNA–AP relationship (peripheral arc) upward without significant changes in slope.

In conclusions, volume loading‐induced acute LPB activation evoked two‐phase changes, an initial increase followed by decline from baseline value, in SNA via resetting of the ABR central arc. LPB may contribute greatly to stabilize AP in response to volume status.

Volume loading‐induced low pressure baroreflex evoked two‐phase changes, an initial increase followed by decline from baseline value, in sympathetic nerve activity via upward or downward resetting of the arterial baroreflex central arc. Fetal insulin is critical for regulation of growth.

Insulin concentrations are partly determined by the amount of ‐cells present and their insulin content. Insulin‐like growth factor‐1 (IGF‐1) is a fetal anabolic growth factor which also impacts ‐cell mass in models of ‐cell injury and diabetes.

The extent to which circulating concentrations of IGF‐1 impact fetal ‐cell mass and pancreatic insulin content is unknown. We hypothesized that an infusion of an IGF‐1 analog for 1 week into the late gestation fetal sheep circulation would increase ‐cell mass, pancreatic islet size, and pancreatic insulin content.

After the 1‐week infusion, pancreatic insulin concentrations were 80% higher than control fetuses (P< 0. 05), but there were no differences in ‐cell area, ‐cell mass, or pancreatic vascularity.

However, pancreatic islet vascularity was 15% higher in IGF‐1 fetuses and pancreatic VEGFA, HGF, IGF1, and IGF2 mRNA expressions were 70–90% higher in IGF‐1 fetuses compared to control fetuses (P< 0. Plasma oxygen, glucose, and insulin concentrations were 25%, 22%, and 84% lower in IGF‐1 fetuses, respectively (P< 0. The previously described role for IGF‐1 as a ‐cell growth factor may be more relevant for local paracrine signaling in the pancreas compared to circulating endocrine signaling. We determined the effect of a 1‐week infusion of an IGF‐1 agonist into fetal sheep on the fetal pancreas.

While fetal plasma insulin concentrations decreased, fetal pancreatic insulin concentrations increased. Furthermore, fetal pancreatic islet vascularity and the expression of several growth factors within the fetal pancreas also were increased.

Noninvasive imaging of the murine pulmonary vasculature is challenging due to the small size of the animal, limits of resolution of the imaging technology, terminal nature of the procedure, or the need for intravenous contrast. We report the application of laboratory-based high-speed, high-resolution x-ray imaging, and image analysis to detect quantitative changes in the pulmonary vascular tree over time in the same animal without the need for intravenous contrast.

Using this approach, we detected an increased number of vessels in the pulmonary vascular tree of animals after 30 min of recovery from a brief exposure to inspired gas with 10% oxygen plus 5% carbon dioxide (mean ± standard deviation: 2193 ± 382 at baseline vs. In a separate set of animals, we showed that the total pulmonary blood volume increased (P = 0.

0412) while median vascular diameter decreased from 0. 0436) over the respiratory cycle from end-expiration to end-inspiration.

These findings suggest that the noninvasive, nonintravenous contrast imaging approach reported here can detect dynamic responses of the murine pulmonary vasculature and may be a useful tool in studying these responses in models of disease. Aging is associated with pulmonary vascular remodeling and reduced distensibility.

We investigated the influence of aging on changes in cardiac output (Q), mean pulmonary artery pressure (mPAP), and lung diffusing capacity in response to alterations in thoracic blood volume. The role of pulmonary smooth muscle tone was also interrogated via pulmonary vasodilation.

Nine younger (27 ± 4 years) and nine older (71 ± 4 years) healthy adults reached steady-state in a Supine (0°), Upright (+20°), or Head-down (-20°) position in order to alter thoracic blood volume. In each position, echocardiography was performed to calculate mPAP and Q, and lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO) was assessed.

Next, 100 mg sildenafil was administered to reduce pulmonary smooth muscle tone, after which the protocol was repeated. 032) were lower in the Upright versus Supine and Head-down positions, and mPAP was reduced following sildenafil administration (P = 0.

SV was lower in the Upright versus Supine and Head-down positions in both younger (P ≤ 0.

DLCO and DLNO were not greatly altered by position changes or sildenafil administration. However, the DLNO/DLCO ratio was lower in the Supine and/or Head-down positions (P ≤ 0.

05), but higher following sildenafil administration (P ≤ 0. In conclusion, older adults experience greater cardiopulmonary alterations following thoracic blood volume changes, and pulmonary smooth muscle tone plays a role in resting mPAP in older adults only. Furthermore, mPAP is an important determinant of pulmonary capillary blood volume distribution (DLNO/DLCO), regardless of age.

Premature infants have a high incidence of bronchopulmonary dysplasia (BPD). Systemic hypertension, arterial thickness and stiffness, and increased systemic afterload may all contribute to BPD pathophysiology by altering left ventricular (LV) function and increasing pulmonary venous congestion by lowering end‐diastolic compliance.

This case series studied the usefulness of angiotensin‐converting enzyme (ACE) inhibition by measuring clinical and echocardiographic improvements in six consecutive infants with “severe” BPD unresponsive to conventional therapy. The range of gestation and birthweight were 23–29 weeks and 505–814 g, respectively.

All required mechanical ventilation (including high‐frequency oscillation) and all but one were administered postnatal corticosteroids. Other treatments including sildenafil and diuretics made no clinical improvements.

Captopril was started for systemic hypertension after cardiac and vascular ultrasounds which were repeated 5 weeks later. A significant reduction in oxygen (55 ± 25 to 29 ± 3%, two‐tailed P = 0.

03) and ventilator requirements, and improved cardiovascular parameters were noted. This included a trend toward reduction in aorta intima media thickness 840 ± 94 to 740 ± 83 m, P = 0.

07 and an increased pulsatile diameter 36 ± 14 to 63 ± 25 m, P = 0. Improvements were observed for both systolic (increased LV output, 188 ± 13 to 208 ± 13 mL/kg/min, P = 0. 046 and mean velocity of circumferential fiber shortening, 1.

0004) and diastolic (decreased isovolumic relaxation time, 69. 044) function which was accompanied by increased pulmonary vein flow. Right ventricular output increased accompanied by a significant lowering of pulmonary vascular resistance.

These findings suggest that improving respiratory and cardiac indices (especially diastolic function) warrants further exploration of ACE inhibition in BPD infants unresponsive to conventional therapy. While bronchopulmonary dysplasia is the most common respiratory sequelae of preterm birth, contribution of systemic arterial thickness/stiffness to its pathophysiology is not well appreciated.

This article demonstrates the usefulness of systemic afterload reduction using an angiotensin‐converting enzyme inhibitor (ACE, captopril) in a cohort of infants with “severe” BPD, unresponsive to standard therapy. The role of ACE inhibitors beyond the reduction in blood pressure is discussed.

The aim of this study was to determine the effect of season on diurnal rhythms of heart (HR) and respiratory rates (RespR) in the adult, yearling, and foal donkeys during the cold-dry and hot-dry seasons under natural light/dark cycle. The resting HR and RespR were recorded bihourly for 24 consecutive hours from 06:00 to 06:00 h (GMT +1) in 30, clinically healthy donkeys (10 adults,10 yearlings, and 10 foals).

Dry-bulb temperature (DBT), relative humidity (RH), temperature-humidity index (THI) and wet-bulb globe temperature index (WBGT) inside the pen were recorded bihourly from 06:00 to 06:00 h. Values of DBT, THI, and WBGT obtained during the hot-dry season were significantly (P< 0.

05) higher than corresponding values recorded during the cold-dry season. Application of single-cosinor procedure showed that HR and RespR exhibited daily rhythmicity in both seasons.

40 bpm) donkeys during the cold-dry season were significantly (P< 0. 01) lower, compared to the corresponding values of 48.

The mesors of RespR in adult, yearling, and foal donkeys during the hot-dry season were higher (P< 0. 05), when compared to the corresponding values recorded in the cold-dry season.

The HR and RespR of foals were significantly (P< 0. 05) higher than those of the adult and yearling donkeys.

Amplitudes of HR and RespR were higher during the hot-dry season than the cold-dry season. In conclusion, seasonal changes affect diurnal rhythmicity of HR and RespR of adult, yearling, and foal donkeys during the cold-dry and hot-dry seasons.

The HR and RespR of donkeys vary with age, with higher values in the foals than the adult and yearling donkeys in both seasons. Renal ischemia‐reperfusion (IR) injury and acute kidney injury (AKI) increase the risk of developing hypertension, with T cells suspected as a possible mechanistic link.

Endothelin promotes renal T cell infiltration in several diseases, predominantly via the ETA receptor, but its contribution to renal T cell infiltration following renal IR injury is poorly understood. To test whether ETA receptor activation promotes T cell infiltration of the kidney following IR injury, male C57BL/6 mice were treated with the ETA receptor antagonist ABT‐627 or vehicle, commencing 2 days prior to unilateral renal IR injury.

Mice were sacrificed at 24 h or 10 days post‐IR for assessment of the initial renal injury and subsequent infiltration of T cells. Vehicle and ABT‐627‐treated mice displayed significant upregulation of endothelin‐1 (ET‐1) in the IR compared to contralateral kidney at both 24 h and 10 days post‐IR (P< 0.

Renal CD3+ T cell numbers were increased in the IR compared to contralateral kidneys at 10 days, but ABT‐627‐treated mice displayed a 35% reduction in this effect in the outer medulla (P< 0.

vehicle) and a nonsignificant 23% reduction in the cortex compared to vehicle‐treated mice.

Whether specific T cell subsets were affected awaits confirmation by flow cytometry, but outer medullary expression of the T helper 17 transcription factor ROR t was reduced by ABT‐627 (P = 0. These data indicate that ET‐1 acting via the ETA receptor contributes to renal T cell infiltration post‐IR injury. This may have important implications for immune system‐mediated long‐term consequences of AKI, an area which awaits further investigation.

Endothelin promotes renal T cell infiltration in several chronic disease states, predominantly via the ETA receptor. The current study demonstrates that ETA receptor activation also promotes renal T cell infiltration following unilateral renal ischemia‐reperfusion injury.

We present data from two experiments that examined how the developmental processes of smoltification and sexual maturation proceed in parallel in domesticated Atlantic salmon. Onset of maturation and smoltification was stimulated using temperature and photoperiod.

Our observations on gonadosomatic index (GSI), spermatogenic activity, gill Na+, K+‐ATPase enzyme (NKA) activity, and plasma 11‐ketotestosterone (11‐KT), Na, Cl, and Ca show that smoltification and maturation were both triggered and developed in parallel in male Atlantic salmon, but that the progressing maturation impaired hypoosmoregulation. Female maturation started after completion of smoltification.

Furthermore, we present data showing that domesticated salmon can physiologically smoltify–desmoltify–resmoltify within a short period of time, and that development of a secondary sexual characteristic, such as a kype, depends on size in male postsmolts. The study shows that smoltification and maturation can develop in parallel and without conflicting in male Atlantic salmon.

However, with time, maturation impaired hypoosmoregulation. Moreover, physiological smoltification–desmoltification–resmoltification were observed within a short time period, showing the plasticity and robustness of the osmoregulatory system in domesticated salmon.

The effect of high‐intensity training (HIT) on mitochondrial ADP sensitivity and respiratory capacity was investigated in human skeletal muscle and subcutaneous adipose tissue (SAT). Twelve men and women underwent 6 weeks of HIT (7 × 1 min at app.

Mitochondrial respiration was measured in permeabilized muscle fibers and in abdominal SAT.

Mitochondrial ADP sensitivity was determined using Michaelis Menten enzyme kinetics. VO2max, body composition and citrate synthase (CS) activity (skeletal muscle) and mtDNA (SAT) were measured before and after training.

011) accompanied by a decreased mitochondrial ADP sensitivity in skeletal muscle (Km: 0.

Mitochondrial respiratory capacity increased in skeletal muscle from 57 ± 4 to 67 ± 4 pmol O2·mg−1·sec−1 (P< 0. Intrinsic mitochondrial respiratory capacity was unchanged in skeletal muscle, but increased in SAT after HIT.

In summary, our results demonstrate that mitochondrial adaptations to HIT in skeletal muscle are comparable to adaptations to endurance training, with an increased mitochondrial respiratory capacity and CS activity. However, mitochondria in SAT adapts differently compared to skeletal muscle mitochondria, where mitochondrial respiratory capacity decreased and mtDNA remained unchanged after HIT.

The effect of high‐intensity training on adipose tissue and skeletal muscle mitochondrial function. Shift in the cellular homeostasis of the organic osmolyte taurine has been associated with dysregulation of the volume-regulated anion channel (VRAC) complex, which comprises leucine-rich repeat-containing family 8 members (LRRC8A-E).

Using SDS-PAGE, western blotting, qRT-PCR, and tracer technique ( 3 H taurine) we demonstrate that reactive oxygen species (ROS) and the cell growth-associated kinases Akt/mTOR, play a role in the regulation of VRAC in human alveolar cancer (A549) cells. LRRC8A is indispensable for VRAC activity and long-term exposure to hypoosmotic challenges and/or ROS impairs VRAC activity, not through reduction in total LRRC8A expression or LRRC8A availability in the plasma membrane, but through oxidation/inactivation of kinases/phosphatases that control VRAC activity once it has been instigated.

Pursuing Akt signaling via the serine/threonine kinase mTOR, using mTORC1 inhibition (rapamycin) and mTORC2 obstruction (Rictor knockdown), we demonstrate that interference with the PI3K-mTORC2-Akt signaling-axes obstructs stress-induced taurine release. Furthermore, we show that an increased LRRC8A expression, following exposure to cisplatin, ROS, phosphatase/lipoxygenase inhibitors, and antagonist of CysLT1-receptors, correlates an increased activation of the proapoptotic transcription factor p53.

It is suggested that an increase in LRRC8A protein expression could be taken as an indicator for cell stress and limitation in VRAC activity. The glucose transporter 4 (Glut4) mediates insulin‐dependent glucose uptake.

Glut4 expression levels are correlated with whole‐body glucose homeostasis. Insulin signaling is known to recruit Glut4 to the cell surface.

Expression of Glut4 is subject to tissue‐specific hormonal and metabolic regulation. The molecular mechanisms regulating skeletal muscle Glut4 expression remain to be elucidated.

Myostatin (Mstn) is reported to be involved in the regulation of energy metabolism. While elevated Mstn levels in muscle are associated with obesity and type‐2 diabetes in both human and mouse models, Mstn null mice exhibit immunity to dietary‐induced obesity and insulin resistance.

The molecular mechanisms by which Mstn initiates the development of insulin resistance and disorders of glucose disposal are not well delineated. Here we investigated effects of Mstn on insulin action in C2C12 cells.

Mstn significantly reduced basal and insulin‐induced IRS‐1 tyrosine (Tyr495) phosphorylation, and expression and activation of PI3K, associated with diminished AKT phosphorylation and elevated GSK3 phosphorylation at Ser9. In addition, Mstn inhibited Glut4 mRNA and protein expression, and reduced insulin‐induced Glut4 membrane translocation and glucose uptake.

Conversely, SB431542, a Smad2/3 inhibitor, significantly increased cellular response to insulin. Mstn decreased AMP‐activated protein kinase (AMPK) activity accompanied by reduced Glut4 gene expression and glucose uptake, which were partially reversed by AICAR, an AMPK activator.

These data suggest that Mstn inhibits Glut4 expression and insulin‐induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin‐desensitizing effect and indirect suppression of AMPK activation. The manuscript addresses cellular and molecular mechanisms that underlie the association between myostatin and insulin resistance using C2C12 myoblasts.

Whether this is linked to maladaptation's in skeletal muscle mitochondrial function and in particular to the level of reactive oxygen species (ROS) is at present unknown.

The aim of this longitudinal study was to quantify skeletal muscle mitochondrial function (respiratory capacity and ROS production) together with glucose tolerance after 4 days of strict bed rest in healthy young male subjects (n = 14). Mitochondrial function was determined in permeabilized muscle fibers using high‐resolution respirometry and fluorometry, mitochondrial content (citrate synthase CS activity) and antioxidant protein expression levels were assessed in parallel to this.

Glucose tolerance was determined by means of oral glucose tolerance tests. Intrinsic mitochondrial respiratory capacity was augmented after the bed rest period (CI + IIP: 0.

14 pmol/sec/mg /CS activity), due to a decreased CS activity (158 ± 39 vs. No differences were observed in ROS production (per mg of tissue or when normalized to CS activity).

Furthermore, the protein content for catalase was increased while superoxide dismutase and glutathione peroxidase remained unaffected. These findings were accompanied by an impaired glucose tolerance after the bed rest period (Matsuda index: 12 ± 6 vs.

The change in intrinsic mitochondrial respiratory capacity could be an early indication in the development of impaired glucose tolerance.

The increased catalase protein content might explain that no change was seen in ROS production after 4 days of bed rest. Whether these findings can be extrapolated to lifestyle‐dependent decrements in physical activity and the development of type‐2‐diabetes remains unknown.

Intrinsic mitochondrial respiratory capacity is increased after 4 days of bed rest. Leg immersion in carbonated water improves endothelial‐mediated vasodilator function and decreases arterial stiffness but the mechanism underlying this effect remains poorly defined.

We hypothesized that carbonated water immersion increases muscle blood flow. To test this hypothesis, 10 men (age 21 ± 0 years; mean ± SD) underwent lower leg immersion in tap or carbonated water at 38°C.

We evaluated gastrocnemius muscle oxyhemoglobin concentration and tissue oxygenation index using near‐infrared spectroscopy, skin blood flow by laser Doppler flowmetry, and popliteal artery (PA) blood flow by duplex ultrasound. Immersion in carbonated, but not tap water elevated PA (from 38 ± 14 to 83 ± 31 mL/min; P< 0.

In contrast, lower leg immersion elevated oxyhemoglobin concentration and tissue oxygenation index with no effect of carbonation (P = 0. In addition, the change in PA blood flow in response to immersion in carbonated water correlated with those of skin blood flow (P = 0.

136) while no relations was found for tap water immersion. These findings indicate that water carbonation has minimal effect on muscle blood flow.

Furthermore, PA blood flow increases in response to lower leg immersion in carbonated water likely due to a large increase in skin blood flow. Leg immersion in water at 38°C increased muscle blood flow with small effect of water carbonation.

Yet, water carbonation greatly increased skin blood flow whereby the improvement in vascular function in response to immersion in carbonated water likely relates to changes in the cutaneous vasculature rather than muscle blood flow. An active lifestyle is generally recommended for hypertensive patients to prevent subsequent end‐organ damage.

However, experimental data on long‐term effects of exercise on hypertension are insufficient and underlying mechanisms are not well understood. This study was aimed to investigate the effect of exercise on renal expression of parathyroid hormone‐related protein (PTHrP) and parathyroid hormone receptor type 1 (PTHR1) in spontaneously hypertensive rats (SHR).

Twenty‐four rats started free running wheel exercise at the age of 1. 5 months (pre‐hypertensive state) and proceeded for 1.

Thirty rats kept under standard housing conditions were used as sedentary controls. Kidney function was assessed by measuring plasma creatinine levels and urine albumin‐to‐creatinine ratios.

Renal expression of PTHrP and PTHR1 was analyzed by qRT‐PCR and western blot. Renal expression of PTHR1 was markedly increased between the 6th and 10th months in sedentary rats and this increase was significantly lower in SHRs with high physical activity on mRNA (−30%) and protein level (−27%).

At the same time, urine albumin‐to‐creatinine ratio increased (from 65 to 231 mg/g) but somehow lower in exercise performing SHRs (48–196 mg/g). Our data suggest that enhanced exercise, stimulated by allocation of a free running wheel, is associated with lower PTHR1 expression in SHRs and this may contribute to preserved kidney function.

Using an established model of essential hypertension (spontaneously hypertensive rats) we show that the renal expression of PTHrP receptor 1 increases at a time where mild proteinuria occurs. High physical activity, starting already at a pre‐hypertensive state, significantly reduced renal expression of PTHrP receptor 1 (mRNA and protein), and slightly reduces proteinuria in these rats.

Our study provides evidence that high physical activity attenuates renal disease in chronic hypertension. The aim of this study was to examine whether thermal pretreatment can accelerate recovery from prolonged low‐frequency force depression.

The hindlimbs of thermal treated (T‐treated) rats were immersed in water heated to 42. The thermal pretreatment was performed once a day for 5 days before fatiguing stimulation.

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Using skinned fiber prepared from the superficial region, the ratio of force at 1 Hz to that at 50 Hz (low‐to‐high force ratio), the ratio of depolarization (depol)‐induced force to maximum Ca2+‐activated force (depol/max Ca2+ force ratio), the steepness of force‐Ca2+ concentration curves, and myofibrillar Ca2+ sensitivity were measured.

At REC0, the low‐to‐high force ratio and depol/max Ca2+ force ratio decreased in stimulated muscles from both non‐ and thermal‐treated rats 2 May 2007 - Lead for Physiological Measurement, Department of Health. Physiological new emphasis to the range of skills needed across the in order to deliver 18 week pathways. The or in reporting and interpreting). In some..

At REC60, these two parameters remained depressed in non‐treated rats, whereas they reverted to resting levels in T‐treated rats. Thermal pretreatment exerted no effect on myofibrillar Ca2+ sensitivity.

The present results reveal that thermal pretreatment can facilitate recovery of submaximum force after vigorous contraction, which is mediated via a quick return of Ca2+ release from the sarcoplasmic reticulum to resting levels. Before fatiguing contraction, the hindlimbs of rats were immersed to hot water (thermal pretreatment).

The thermal pretreatment can facilitate recovery from prolonged low‐frequency force depression. Mice with a deletion of the p50 subunit of the proinflammatory nuclear factor kappa B pathway (NF‐ B p50) have reduced weight compared to wild‐type control mice.

However, the physiological underpinning of this phenotype remains unknown. Compared to littermate controls, lean male p50 null mice (p50−/−) had an increased metabolic rate (~20%) that was associated with increased skeletal muscle (SkM, ~35%), but not liver, oxidative metabolism. These metabolic alterations were accompanied by decreases in adiposity, and tissue and plasma triglyceride levels (all ~30%).

Notably, there was a marked decrease in skeletal muscle, but not liver, DGAT2 gene expression (~70%), but a surprising reduction in muscle PPAR and CPT1 (both ~20%) gene expression. Exposure to a high‐fat diet accentuated the diminished adiposity of p50−/− mice despite elevated caloric intake, whereas plasma triglycerides and free fatty acids (both ~30%), and liver (~40%) and SkM (~50%) triglyceride accumulation were again reduced compared to WT.

Although SkM cytokine expression (IL‐6 and TNF , each ~100%) were increased in p50−/− mice, neither cytokine acutely increased SkM oxidative metabolism. We conclude that the reduced susceptibility to diet‐induced obesity and dyslipidemia in p50−/− mice results from an increase in metabolic rate, which is associated with elevated skeletal muscle oxidative metabolism and decreased DGAT2 expression.

Our study addresses the mechanisms of reduced weight gain of NFkappaB‐p50 null mice compared to wild‐type mice on a high‐fat diet. Our data demonstrate that the p50−/− mice have an increase in metabolic rate, which is associated with elevated skeletal muscle oxidative metabolism, increased inflammation, decreased DGAT2 expression, and improved lipid profiles, and manifests as a reduced susceptibility to obesity.

Erythropoietin (EPO) acts on erythroid progenitor cells to promote their survival and differentiation to mature erythrocytes. Along with this canonical role, EPO is also reported to modulate energy metabolism, resulting in improved glucose tolerance and insulin sensitivity.

EPO also stimulates the production of the hormone erythroferrone (ERFE) which acts to suppress hepcidin production, thus increasing dietary iron absorption and mobilizing stored iron for use in erythropoiesis. ERFE (initially termed myonectin) was also reported have an effect on systemic lipid metabolism by promoting the clearance of nonesterifed fatty acids (NEFA) from circulation.

As increased levels of circulating NEFA blunt insulin sensitivity and impair glucose tolerance, ERFE-induced clearance of NEFA after EPO administration would have a beneficial effect on glucose metabolism. The aim of this study was to determine if the known metabolic effect of EPO treatment on glucose homeostasis is mediated by ERFE, produced in response to EPO.

Mice lacking Erfe did not differ from wild-type mice in blood lipid parameters, blood glucose, and glucose or insulin tolerance at baseline or after chronic EPO treatment. Additionally, hepcidin suppression and the response of erythrocyte parameters to chronic EPO treatment were unaffected by the absence of Erfe.

These findings suggest that the known beneficial effects of EPO on glucose metabolism are not attributable to an accompanying increase in ERFE production, and that Erfe is dispensable for normal glucose homeostasis. Furthermore, our data indicate that ERFE-independent mechanisms can suppress hepcidin in response to chronically elevated EPO levels.

Loss of muscle mass and function are a well-defined aspect of human aging from the 3rd decade of life, which result in reduced independence and increased mortality. The activin family of peptides contains several endocrine factors (activin A, myostatin, growth and differentiation factor 11 GDF11 ) that may play roles in changes in muscle mass and the aging process, however, it may be simplistic to consider aging as a result of a single peptides changes.

Thus, we aimed to examine changes in activin family members across a cohort of healthy individuals of various ages, hypothesizing that these would aid predictive models of age and functional measures of age. Healthy participants (n = 88) were recruited and resting metabolic rate, body composition, grip strength, walking speed, and circulating plasma concentrations of myostatin (total and free), activin A, follistatin-like binding protein (FLRG), and GDF11 quantified.

Simple regressions between circulating factors and chronological age, grip strength, and walking speed were examined. Multiple stepwise regressions for age, grip strength, and walking speed are also reported.

Age negatively correlated with total myostatin (P = 0. 053), grip strength positively with activin A (P = 0. 048), whereas walking speed showed no simple regression relationships. Stepwise regressions suggested a role of total myostatin and activin A in models of age, whereas GDF11 contributed to the model of grip strength.

Here we suggest a role for myostatin, activin A, and GDF11 in normal human aging that mirrors animal studies to date. Further interventional studies are required to elicitate the physiological role of these changes in the normal human aging process, and indeed if offsetting these changes can promote successful aging.

The mechanism by which heart rate (HR) control with esmolol improves hemodynamics during septic shock remains unclear. Improved right ventricular (RV) function, thereby reducing venous congestion, may play a role.

We assessed the effect of HR control with esmolol during sepsis on RV function, macrocirculation, microcirculation, end‐organ‐perfusion, and ventricular‐arterial coupling. Sepsis was induced in 10 healthy anesthetized and mechanically ventilated sheep by continuous IV administration of lipopolysaccharide (LPS).

Esmolol was infused after successful resuscitation of the septic shock, to reduce HR and stopped 30‐min after reaching targeted HR reduction of 30%. Venous and arterial blood gases were sampled and the small intestines’ microcirculation was assessed by using a hand‐held video microscope (CytoCam‐IDF).

Arterial and venous pressures, and cardiac output (CO) were recorded continuously. An intraventricular micromanometer was used to assess the RV function.

Ventricular–arterial coupling ratio (VACR) was estimated by catheterization‐derived single beat estimation. The targeted HR reduction of >30% by esmolol infusion, after controlled resuscitation of the LPS induced septic shock, led to a deteriorated RV‐function and macrocirculation, while the microcirculation remained depressed.

Esmolol improved VACR by decreasing the RV end‐systolic pressure. Stopping esmolol showed the reversibility of these effects on the RV and the macrocirculation.

In this animal model of acute severe endotoxic septic shock, early administration of esmolol decreased RV‐function resulting in venous congestion and an unimproved poor microcirculation despite improved cardiac mechanical efficiency. In this paper, we showed that esmolol decreased RV function resulting in reduced perfusion pressure, venous congestion, and an unimproved poor microcirculation despite improved cardiac mechanical efficiency in early experimental endotoxic shock.

The spatio-temporal convergent (STC) response occurs in central vestibular cells when dynamic and static inputs are activated. The functional significance of STC behavior is not fully understood.

Whether STC is a property of some specific central vestibular neurons, or whether it is a response that can be induced in any neuron at some frequencies is unknown. It is also unknown how the change in orientation of otolith polarization vector (orientation adaptation) affects STC behavior.

A new complex model, that includes inputs with regular and irregular discharges from both canal and otolith afferents, was applied to experimental data to determine how many convergent inputs are sufficient to explain the STC behavior as a function of frequency and orientation adaptation. The canal-otolith and otolith-only neurons were recorded in the vestibular nuclei of three monkeys.

About 42% (11/26 canal-otolith and 3/7 otolith-only) neurons showed typical STC responses at least at one frequency before orientation adaptation. After orientation adaptation in side-down head position for 2 h, some canal-otolith and otolith-only neurons altered their STC responses.

Thus, STC is a property of weights of the regular and irregular vestibular afferent inputs to central vestibular neurons which appear and/or disappear based on stimulus frequency and orientation adaptation. This indicates that STC properties are more common for central vestibular neurons than previously assumed.

While gravity-dependent adaptation is also critically dependent on stimulus frequency and orientation adaptation, we propose that STC behavior is also linked to the neural network responsible for localized contextual learning during gravity-dependent adaptation. Sedentarism is one of the main risk factors for the onset of cardiometabolic diseases.

Some biomarkers, such as heart rate variability (HRV), have been largely studied and found to be involved in the genesis of the dysfunctions associated with sedentary behavior. However, comparatively few studies have focused on the female sex.

The objective of this study was to analyze the hemodynamic, autonomic and quality of life parameters at rest and in response to mental stress of sedentary and physically active young women. A total of 96 women, 18–30 years of age, were divided into sedentary (SW = 48) and active (AW = 48) groups.

Anthropometric, hemodynamic and quality of life parameters were evaluated and the R‐R interval was recorded to quantify the cardiac autonomic modulation at rest and in response to the Stroop Color Test. The groups were similar in age, weight, height, body mass index, fat percentage, systolic and diastolic blood pressure values and glycemia.

The physical health domain of quality of life was compromised in the SW group. The SW group presented higher heart rate, lower variance of RR interval and RMSSD and higher cardiac sympathovagal balance (LF/HF) both at rest and in response to the mental stress test.

We concluded that sedentary lifestyle in women induces impairment in autonomic cardiac modulation at rest and in response to physiological stress, compromising the quality of life, even before altering any cardiovascular or metabolic clinical parameters, reinforcing the potential role of HRV as early marker of cardiovascular risk in this population. We concluded that sedentary lifestyle in women induces impairment in autonomic cardiac modulation at rest and in response to physiological stress, compromising the quality of life, even before altering any cardiovascular or metabolic clinical parameters, reinforcing the potential role of HRV as early marker of cardiovascular risk in this population.

The aim was to evaluate changes in peripheral and cerebral oxygenation, cardiorespiratory, and performance differences, as well as neuromuscular fatigue across multiple levels of blood flow restriction (BFR) during a repeated cycling sprint test to exhaustion (RST). Participants performed three RST (10-sec maximal sprints with 20-sec recovery until exhaustion) with measurements of power output and V̇O2peak as well as oxygenation (near-infrared spectroscopy) of the vastus lateralis and prefrontal cortex.

Neuromuscular fatigue was assessed by femoral nerve stimulation to evoke the vastus lateralis. Tests were conducted with proximal lower limb bilateral vascular occlusion at 0%, 45%, and 60% of resting pulse elimination pressure.

Decreased changes in muscle deoxyhemoglobin (∆ HHb ) during sprints were demonstrated at 60% compared to 0% (P< 0.

Changes in total hemoglobin concentrations (∆ tHb ) increased at both 45% and 60% compared with 0% (P< 0.

Cerebral ∆ tHb increased toward exhaustion (P< 0.

Maximal voluntary contraction (MVC), voluntary activation level (VAL), and root mean square (RMS)/M-wave ratio decreased at 60% compared with 0% (P< 0.

MVC and VAL decreased between 45% and 60% (P< 0.

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Additionally, high-intensity sprint exercise with partial ischemia may challenge cerebral blood flow regulation and influence local fatigue development due to protection of cerebral function. Inflammation is known to alter nervous system function, but its effect on muscle spindle afferent mechanosensation and sensory integration in the spinal cord has not been well studied.

We tested the hypothesis that systemic inflammation induced by an intraperitoneal injection of the endotoxin lipopolysaccharide (LPS; 7. 5 × 105 endotoxin units/kg 18 h before experiment) would alter muscle spindle afferent mechanosensation and spinal cord excitability to Group Ia input in male and female adult C57Bl/6 mice.

LPS injection caused a systemic immune response, evidenced by decreased white blood cell, monocyte, and lymphocyte concentrations in the blood, increased blood granulocyte concentration, and body weight loss. The immune response in both sexes was qualitatively similar.

We used an in vitro muscle-nerve preparation to assay muscle spindle afferent response to stretch and vibration. LPS injection did not significantly change the response to stretch or vibration, with the exception of small decreases in the ability to entrain to high-frequency vibration in male mice.

Similarly, LPS injection did not alter spinal cord excitability to Group Ia muscle spindle afferent input as measured by the Hoffman's reflex test in anesthetized mice (100 mg/kg ketamine, 10 mg/kg xylazine). Specifically, there were no changes in M or H wave latencies nor in the percentage of motor neurons excited by electrical afferent stimulation (Hmax /Mmax ).

Overall, we found no major alterations in muscle proprioceptor function or sensory integration following exposure to LPS at a dose and time course that causes changes in nociceptor function and central processing. Estradiol plays a critical role in stimulating the fetal hypothalamus-pituitary-adrenal axis at the end of gestation.

Estradiol action is mediated through nuclear and membrane receptors that can be modulated by ICI 182,780, a pure antiestrogen compound. The objective of this study was to evaluate the transcriptomic profile of estradiol and ICI 182,780, testing the hypothesis that ICI 182,780 antagonizes the action of estradiol in the fetal hypothalamus.

Chronically catheterized ovine fetuses were infused for 48 h with: vehicle (Control, n = 6), 17 -estradiol 500 g/kg/day (Estradiol, n = 4), ICI 182,780 5 g/kg/day (ICI 5 g, n = 4) and ICI 182,780 5 mg/kg/day (ICI 5 mg, n = 5). Fetal hypothalami were collected afterward, and gene expression was measured through microarray.

Statistical analysis of transcriptomic data was performed with Bioconductor-R and Cytoscape software. 5% of the upregulated differentially expressed genes (DEG) by Estradiol significantly overlapped (P< 0. 05) with upregulated DEG by ICI 5 mg and ICI 5 g, respectively.

For the downregulated DEG, these percentages were 29. There was almost no overlap for DEG following opposite directions between Estradiol and ICI ICI 5 mg or ICI 5 g.

Furthermore, most of the genes in the estrogen signaling pathway - after activation of the epidermal growth factor receptor - followed the same direction in Estradiol, ICI 5 g or ICI 5 mg compared to Control. In conclusion, estradiol and ICI 182,780 have estrogenic genomic effects in the developing brain, suggesting the possibility that the major action of estradiol on the fetal hypothalamus involves another receptor system rather than estrogen receptors.

This study examined the association between changes in mRNA expression of development-related genes including those of the homeobox (Hox) family and growth-dependent increases in inguinal, mesenteric, and epididymal white adipose tissue (WAT) at 4, 6, 10, and 14 weeks of age in rats. We also examined the effects of a 9-week exercise training regimen starting at 5 weeks of age on the mRNA levels of the genes of interest.

HoxC8, HoxC9, Gpc4, Bmpr1a, Ppar , Pgc1 , Adrb3, Hsl, leptin, and adiponectin in each type of WAT - except HoxA5, Gpc4, and Pgc1 in epididymal - showed a positive association between WAT weights and WAT mRNA levels; however, the slope of the regression lines exhibited fat depot-specific differences. HoxA5 showed no significant association, and Gpc4 and Pgc1 showed a negative association in epididymal WAT.

After exercise training, the mean HoxA5, HoxC8, HoxC9, HoxC10, Gpc4, Ppar , and Pgc1 mRNA levels in inguinal WAT were outliers on the regression line between mean mRNA level and WAT weight in control rats - that is, mean HoxA5 and Pgc1 mRNA level was higher, whereas HoxC8, HoxC9, HoxC10, Gpc4, and Ppar levels were lower in exercise-trained rats than in same-age controls. Ppar and adiponectin levels were upregulated in epididymal WAT, while HoxA5 was downregulated, but HoxC9, Gpc4, Ppar , and adiponectin levels were upregulated in mesenteric WAT.

These results suggest that some of the developmental genes tested may have fat depot-specific roles in the growth-dependent expansion of WAT, and that Hox genes that are activated in response to exercise training also vary among different WAT types. Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.

, BKCa ) potassium channels which leads to membrane depolarization, voltage-gated Ca-entry, and neurosecretion.

Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and Ca2+ i -signaling in isolated neonatal rat type-1 cells. PK-THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L).

A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK-THPP, A1899 and Ml 365 all evoked a rapid increase in type-1 cell Ca2+ i .

These Ca2+ i responses were abolished in Ca2+ -free solution and greatly attenuated by Ni2+ (2 mM) suggesting that depolarization and voltage-gated Ca2+ -entry mediated the rise in Ca2+ i. Doxapram (50 mol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased Ca2+ i.

We also tested the effects of combined inhibition of BKCa and TASK channels.

TEA (5 mmol/L) slightly increased Ca2+ i in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased Ca2+ i in the presence of A1899 but not in the presence of PK-THPP.

In general Ca2+ i responses to TASK inhibitors, alone or in combination with BKCa inhibitors, were smaller than the Ca2+ i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca2+ -entry but suggest that this, even with concomitant inhibition of BKCa channels, may be insufficient to account fully for the Ca2+ i -response to hypoxia.

Hemodialysis patients have dysfunctional immune systems, chronic inflammation and comorbidity-associated risks of cardiovascular disease (CVD) and infection. Microparticles are biologically active nanovesicles shed from activated endothelial cells, immune cells, and platelets; they are elevated in hemodialysis patients and are associated with chronic inflammation and predictive of CVD mortality in this group.

Exercise is advocated in hemodialysis to improve cardiovascular health yet acute exercise induces an increase in circulating microparticles in healthy populations. Therefore, this study aimed to assess acute effect of intradialytic exercise (IDE) on microparticle number and phenotype, and their ability to induce endothelial cell reactive oxygen species (ROS) in vitro.

Eleven patients were studied during a routine hemodialysis session and one where they exercised in a randomized cross-over design. Microparticle number increased during hemodialysis (2064-7071 microparticles/ L, P< 0.

01) and percentage procoagulant neutrophil-derived microparticles (P< 0. However, microparticles collected immediately and 60 min after IDE (but not later) induced greater ROS generation from cultured endothelial cells (P< 0. 05), suggesting a transient proinflammatory event.

In summary IDE does not further increase prothrombotic microparticle numbers that occurs during hemodialysis. However, given acute proinflammatory responses to exercise stimulate an adaptation toward a circulating anti-inflammatory environment, microparticle-induced transient increases of endothelial cell ROS in vitro with IDE may indicate the potential for a longer-term anti-inflammatory adaptive effect.

These findings provide a crucial evidence base for future studies of microparticles responses to IDE in view of the exceptionally high risk of CVD in these patients. Atrial fibrosis can be estimated noninvasively by magnetic resonance imaging (MRI) using late gadolinium enhancement (LGE), but diastolic dysfunction is clinically assessed by transthoracic echocardiography (TTE), and rarely by MRI.

This study aimed to evaluate well-established diastolic parameters using MRI, and validate them with TTE and left ventricular (LV) filling pressures, and to study the relationship between left atrial (LA) remodeling and parameters of diastolic function. The study retrospectively included 105 patients (53 ± 16 years, 39 females) who underwent 3D LGE MRI between 2012 and 2016.

Medical charts were reviewed for the echocardiographic diastolic parameters E, A, and e' by TTE, and pressure catheterizations. E and A were measured from in-plane phase-contrast cardiac MRI images, and e' by feature-tracking, and validated with TTE.

Interobserver and intraobserver variability was examined. Furthermore, LA volumes, function, and atrial LGE was correlated with diastolic parameters.

Evaluation of e' in MRI had strong agreement with TTE (r = 0. 0001), and low interobserver and intraobserver variability. E and A by TTE showed strong agreement to MRI (r = 0.

Agreement between E/e' by TTE and MRI was strong (r = 0. 0004), and E/e' by TTE correlated moderately to invasive pressures (r = 0. There was a strong relationship between LA LGE and pulmonary capillary wedge pressure (r = 0.

In conclusion, diastolic parameters can be measured with good reproducibility by cardiovascular MRI. LA LGE exhibited a strong relationship with pulmonary capillary wedge pressure, an indicator of diastolic function.

This article examines the central role of Na,K‐ATPase ( 1 1FXYD2) in renal Mg handling, especially in distal convoluted tubule (DCT), the segment responsible for final regulation of Mg balance. By considering effects of Na,K‐ATPase on intracellular Na and K concentrations, and driving forces for Mg transport, we propose a consistent rationale explaining basal Mg reabsorption in DCT and altered Mg reabsorption in some human diseases.

FXYD2 ( subunit) is a regulatory subunit that adapts functional properties of Na,K‐ATPase to cellular requirements. Mutations in FXYD2 (G41R), and transcription factors (HNF‐1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria.

These mutations result in impaired interactions of FXYD2 with Na,K‐ATPase. Renal Mg wasting implies that Na,K‐ATPase is inhibited, but in vitro studies show that FXYD2 itself inhibits Na,K‐ATPase activity, raising K0.

However, FXYD2 also stabilizes the protein by amplifying specific interactions with phosphatidylserine and cholesterol within the membrane.

Renal Mg wasting associated with impaired Na,K‐ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K‐ATPase. We consider also the role of the Na,K‐ATPase in Mg (and Ca) handling in Gitelman syndrome and Familial hyperkalemia and hypertension (FHHt).

Renal Mg handling serves as a convenient marker for Na,K‐ATPase activity in DCT. Renal Mg balance is regulated mainly in the distal convoluted tubule (DCT).

This article discusses detailed molecular and cellular mechanisms by which Na,K‐ATPase activity in DCT determines Mg transport in normal kidneys and in disease states that affect Mg balance (FXYD2 and HNF‐B1 mutations, Gitelmans syndrome, Familial Hyperkalemia and Hypertension (FHHt)). G i2, a heterotrimeric G‐protein subunit, regulates various cell functions including ion channel activity, cell differentiation, proliferation and apoptosis.

Platelet‐expressed G i2 is decisive for the extent of tissue injury following ischemia/reperfusion.

However, it is not known whether G i2 plays a role in the regulation of platelet apoptosis, which is characterized by caspase activation, cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) translocation to the platelet surface Plant & Cell Physiology (PCP) is an international journal that publishes high quality, original articles reporting significant findings in broad aspects of plant Each author should have participated sufficiently in the work to take public The order of authorship should be a joint decision of the co-authors agreed at the outset..

Stimulators of platelet apoptosis include thrombin and collagen‐related peptide (CoRP), which are further known to enhance degranulation and activation of IIb 3‐integrin and caspases. Using FACS analysis, we examined the impact of agonist treatment on activation and apoptosis in platelets drawn from mice lacking G i2 and their wild‐type (WT) littermates.

01 U/mL) or CoRP (2 g/mL or 5 g/mL) significantly upregulated PS‐exposure and significantly decreased forward scatter, reflecting cell size, in both genotypes.

Exposure to CoRP triggered a significant increase in active caspase 3, ceramide formation, surface P‐selectin, and IIb 3‐integrin activation. These molecular alterations were significantly less pronounced in G i2‐deficient platelets as compared to WT platelets.

In conclusion, our data highlight a previously unreported role of G i2 signaling in governing platelet activation and apoptosis. Our current observations shed light on a previously unreported function of platelet G i2 protein, that is, the regulation of platelet survival, mediated, at least partially by agonist‐sensitive ceramide formation.

Our data on G i2‐mediated platelet survival may further our understanding into the thrombo‐inflammatory role of this protein. During fasting, most tissues including skeletal muscle heavily rely on utilization of fatty acids (FA) and minimize glucose use.

In contrast, skeletal muscle prefers carbohydrate use as exercise intensity increases. In mice deficient for CD36 (CD36−/− mice), FA uptake is markedly reduced with a compensatory increase in glucose uptake in skeletal muscle even during fasting.

In this study, we questioned how exercise endurance is affected during prolonged fasting in CD36−/− mice where glucose utilization is constantly increased. With or without a 24‐h fast, a single bout of treadmill exercise was started at the speed of 10 m/min, and the speed was progressively increased up to 30 m/min until mice were exhausted.

Running distance of wild type (WT) and CD36−/− mice was comparable in the fed state whereas that of CD36−/− mice was significantly reduced after a 24‐h fast. Glycogen levels in liver and skeletal muscle were depleted both in WT and CD36−/− mice after a 24‐h fast.

In CD36−/− mice, FA uptake by skeletal muscle continued to be reduced during fasting. Glucose utilization also continued to be enhanced in the heart and oxidative skeletal muscle and glucose supply relative to its demand was diminished, resulting in accelerated hypoglycemia.

Consequently, available energy substrates from serum and in muscle for exercise performance were very limited in CD36−/− mice during prolonged fasting, which could cause a remarkable reduction in exercise endurance. In conclusion, our study underscores the importance of CD36 for nutrient homeostasis to maintain exercise performance of skeletal muscle when nutrient supply is limited.

Running distance of CD36−/− mice was significantly reduced compared with wild type after a 24‐h fast. FA uptake continued to be reduced and hypoglycemia was accelerated during fasting.

Available energy substrates from serum were limited in CD36−/− skeletal muscle, which could cause a remarkable reduction in exercise endurance. The astrocytic glutamate transporter (GLT1) plays an important role in the maintenance of extracellular glutamate concentration below neurotoxic levels in brain.

However, the functional role of GLT1 within the nucleus of the solitary tract (NTS) in the regulation of cardiovascular function remains unclear. We examined the effect of inhibiting GLT1 in the subpostremal NTS on mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA) and heart rate (HR) in anesthetized, artificially ventilated rats.

It was found that dihydrokainate (DHK; inhibitor of GLT1, 5 mmol/L, 100 nL) injections into the NTS (n = 6) decreased MAP (50 ± 10 mmHg, mean ± SD), RSNA (89 ± 14%) and HR (37 ± 6 bpm). Pretreatment with kynurenate (KYN; glutamate receptor antagonist, 5 mmol/L, 30 L) topically applied to the dorsal surface of the brainstem (n = 4) attenuated the responses to NTS injections of DHK (P< 0.

The effect of DHK on arterial baroreflex function was examined using i.

DHK reduced baroreflex response range (maximum-minimum) of RSNA by 91 ± 2% and HR by 83 ± 5% (n = 6, P< 0. These results indicate that inhibition of GLT1 within the NTS decreases MAP, RSNA, and HR by the activation of ionotropic glutamate receptors. As a result, baroreflex control of RSNA and HR was dramatically attenuated.

The astrocytic glutamate transporter in the NTS plays an important role in the maintenance and regulation of cardiovascular function. In arteries, endothelium‐dependent vasodilatory agonists and flow‐induced shear stress cause vasodilation largely by activation of the endothelial enzyme eNOS, which generates nitric oxide that relaxes vascular smooth muscle.

Agonists activate eNOS in part through increased phosphorylation at Ser1179 and decreased phosphorylation at Thr495. We previously found that preconstriction of intact, isolated mouse mesenteric arteries with phenylephrine also caused increased Ser1179 and decreased Thr495 eNOS phosphorylation, and sequential treatment with the vasodilatory agonist acetylcholine did not cause any further change in phosphorylation at these sites, despite producing vasodilation.

The present study tests the hypothesis that luminal flow in these arteries preconstricted with phenylephrine also produces vasodilation without phosphorylation changes at these sites. First‐order mesenteric arteries, isolated from male C57/BL6 mice (7–20 weeks of age) anesthetized with pentobarbital (50 mg/kg, i.

), were cannulated, pressurized, and treated with stepped increases in luminal flow (15–120 L/min).

Flow resulted in dilation that plateaued at ~60 L/min (31. 001) NOS‐dependent at all flow rates (determined by 10⁻ mol/L L‐NAME treatment).

In separate arteries, preconstriction with phenylephrine (10⁻ mol/L) resulted in increased eNOS phosphorylation at Ser1179 (P< 0. 05) and decreased phosphorylation at Thr495, but subsequent flow at 60 L/min for 5 or 15 min did not cause further changes in phosphorylation, despite causing dilation.

Thus, flow‐induced dilation does not require changes in these eNOS phosphorylation sites beyond those induced by alpha1‐adrenergic stimulation with phenylephrine, indicating that eNOS is activated by other mechanisms during acute flow‐induced dilation of preconstricted arteries. Ghrelin is a stomach‐derived hormone that regulates several metabolic functions including growth hormone release, appetite, adiposity, and gastric motility.

Nutrients, the autonomic nervous system, and other metabolic hormones have all been implicated in the regulation of ghrelin secretion. Despite this, ongoing efforts to develop modulators of ghrelin secretion in human diseases are still underway.

Hydrogen sulfide (H2S) is a gaseous signaling molecule that is produced both endogenously in many tissues and by the gut microbiome. H2S has established roles in cardiovascular and immune health, however, more recently H2S has been implicated in the regulation of metabolic hormone secretion.

We hypothesized that H2S is able to directly regulate ghrelin secretion and in turn, regulate appetite. We first demonstrated that GYY4137 (an H2S donor molecule) directly suppresses ghrelin secretion in rat primary gastric culture, in part through the activation of the protein kinase B (AKT) pathway.

We then demonstrated the colocalization of ghrelin‐positive gastric cells with the H2S producing enzyme cystathionine‐ ‐lyase (CSE). While GYY4137 suppressed ghrelin secretion, inhibition of CSE caused a stimulation in ghrelin secretion in primary gastric culture.

In mice, GYY4137 treatment prolonged the postprandial drop of circulating ghrelin and caused reduced food consumption up to 4 h after treatment. These results demonstrate for the first time a role for H2S in the regulation of ghrelin and appetite.

Modulating H2S levels may be a novel approach to regulate ghrelin secretion in the treatment of metabolic diseases. For the first time, the gasotransmitter H2S has been shown to regulate the gastric hormone ghrelin.

H2S was found to directly suppress ghrelin secretion and reduce appetite in mice. Team sports, such as field hockey, incorporate high-intensity repeated sprints, interspersed with low-intensity running, which can result in acidosis.

The aim of the present study was to examine the effect of acute sodium bicarbonate (SB) supplementation on team sport running and skill performance. Eight elite female field hockey players (age 23 ± 5 years, body mass 62.

05 m) completed three Field Hockey Skill Tests (FHST) interspersed with four sets of the Loughborough Intermittent Shuttle Test (LIST).

Prior to exercise, participants were supplemented with capsules equivalent to 0. 2 g·kg-1 body mass (BM) of a placebo (maltodextrin) or 0.

Field hockey skill performance incorporated overall performance time (PFT), movement time (MT), decision-making time (DMT), and penalty time (PT).

Sprint time (ST), rating of perceived exertion (RPE), blood lactate concentration, bicarbonate anion ( HCO3- ) concentration, pH, and base excess were measured at various time points. Data (mean ± SD) were analyzed using a two-way analysis of variance (ANOVA) with repeated measures, with Hedges g effect sizes used to interpret the magnitude of differences.

03) were greater during the bicarbonate trial compared with the placebo (P< 0. RPE was lower during the SB condition (placebo: 13 ± 2; bicarbonate: 12 ± 2, P = 0.

Acute ingestion of bicarbonate did not improve sprint or sport-specific skill performance Physiological data and to prepare the report on the experiment. In order to count average red and white blood cell number, cells have to be treated with a..

Bicarbonate ingestion did result in a lower perception of effort during team-sport running, which may have performance implications in a competitive match situation.

Frontiers in physiology

VOCs generated via metabolic processes are candidate biomarkers of (patho)physiological pathways. We explored the feasibility of using an e-nose to generate human "breathprints" at high altitude.

Furthermore, we explored the hypothesis that pathophysiological processes involved in the development of acute mountain sickness (AMS) would manifest as altered VOC profiles. Breath analysis was performed on Sherpa and lowlander trekkers at high altitude (3500 m).

The Lake Louise Scoring (LLS) system was used to diagnose AMS. Raw data were reduced by principal component (PC) analysis (PCA).

Cross validated linear discriminant analysis (CV-LDA) and receiver-operating characteristic area under curve (ROC-AUC) assessed discriminative function. Breathprints suitable for analysis were obtained from 58% (37/64) of samples.

PCA showed significant differences between breathprints from participants with, and without, AMS; CV-LDA showed correct classification of 83. There were significant differences between breathprints of participants who remained AMS negative and those whom later developed AMS (CV-LDA 68.

PCA demonstrated discrimination between Sherpas and lowlanders (CV-LDA 89. This study demonstrated the feasibility of breath analysis for VOCs using an e-nose at high altitude.

Furthermore, it provided proof-of-concept data supporting e-nose utility as an objective tool in the prediction and diagnosis of AMS. E-nose technology may have substantial utility both in altitude medicine and under other circumstances where (mal)adaptation to hypoxia may be important (e.

Effects of exercise-heat stress with and without water replacement on brain structure and visuomotor performance were examined. 2 years) completed counterbalanced 150 min trials of exercise-heat stress (45°C, 15% RH) with water replacement (EHS) or without (~3% body mass loss; EHS-DEH) compared to seated rest (CON).

Anatomical scans and fMRI Blood-Oxygen-Level-Dependent responses during a visuomotor pacing task were evaluated. Relative to CON, EHS elicited opposing volumetric changes (P< 0. 7%) and periventricular structures (cerebellum: 1.

67) changes, respectively; but, there were no associations (P >0. 50) between structural changes and visuomotor accuracy.

05) within motor and visual areas versus EHS and CON.

Brain structural changes are related to bidirectional plasma osmolality perturbations resulting from exercise-heat stress (with and without water replacement), but do not explain visuomotor impairments. Negative impacts of exercise-heat stress on visuomotor tasks are further exacerbated by dehydration.

The acute respiratory distress syndrome (ARDS) is common in critically ill patients and has a high mortality rate. Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in animal models of ARDS, and their benefits occur in part through interactions with alveolar type II (ATII) cells.

However, the effects that MSCs have on human ATII cells have not been well studied. Using previously published microarray data, we performed genome-wide differential gene expression analyses of human ATII cells that were (1) unstimulated, (2) exposed to proinflammatory cytokines (CytoMix), or (3) exposed to proinflammatory cytokines plus MSCs.

Alveolar type II cells differentially expressed hundreds of genes when exposed either to proinflammatory cytokines or to proinflammatory cytokines plus MSCs.

Stimulation with proinflammatory cytokines increased expression of inflammatory genes and downregulated genes related to surfactant function and alveolar fluid clearance. Some of these changes, including expression of some cytokines and genes related to surfactant, were reversed by exposure to MSCs.

In addition, MSCs induced upregulation of other potentially beneficial genes, such as those related to extracellular matrix remodeling. We confirmed several of these gene expression changes by qPCR.

Thus, ATII cells downregulate genes associated with surfactant and alveolar fluid clearance when exposed to inflammatory cytokines, and mesenchymal stromal cells partially reverse many of these gene expression changes. Calmodulin (CaM) and S100A1 fine-tune skeletal muscle Ca2+ release via opposite modulation of the ryanodine receptor type 1 (RyR1).

Binding to and modulation of RyR1 by CaM and S100A1 occurs predominantly at the region ranging from amino acid residue 3614-3640 of RyR1 (here referred to as CaMBD2). Using synthetic peptides, it has been shown that CaM binds to two additional regions within the RyR1, specifically residues 1975-1999 and 4295-4325 (CaMBD1 and CaMBD3, respectively).

Because S100A1 typically binds to similar motifs as CaM, we hypothesized that S100A1 could also bind to CaMBD1 and CaMBD3. Our goals were: (1) to establish whether S100A1 binds to synthetic peptides containing CaMBD1 and CaMBD3 using isothermal calorimetry (ITC), and (2) to identify whether S100A1 and CaM modulate RyR1 Ca2+ release activation via sites other than CaMBD2 in RyR1 in its native cellular context.

We developed the mouse model (RyR1D-S100A1KO), which expresses point mutation RyR1-L3625D (RyR1D) that disrupts the modulation of RyR1 by CaM and S100A1 at CaMBD2 and also lacks S100A1 (S100A1KO). ITC assays revealed that S100A1 binds with different affinities to CaMBD1 and CaMBD3.

Using high-speed Ca2+ imaging and a model for Ca2+ binding and transport, we show that the RyR1D-S100A1KO muscle fibers exhibit a modest but significant increase in myoplasmic Ca2+ transients and enhanced Ca2+ release flux following field stimulation when compared to fibers from RyR1D mice, which were used as controls to eliminate any effect of binding at CaMBD2, but with preserved S100A1 expression. Our results suggest that S100A1, similar to CaM, binds to CaMBD1 and CaMBD3 within the RyR1, but that CaMBD2 appears to be the primary site of RyR1 regulation by CaM and S100A1.

Diet-induced obesity is associated with hepatic steatosis, which has been linked with activation of the unfolded protein response (UPR). PGC-1 is a transcriptional coactivator involved in exercise training-induced adaptations in muscle and liver.

Therefore, the aim of this study was to test the hypothesis that PGC-1 is required for exercise training-mediated prevention of diet-induced steatosis and UPR activation in liver. Male liver-specific PGC-1 knockout (LKO) and littermate floxed (lox/lox) mice were divided into two groups receiving either control diet (CON) or high-fat high-fructose diet (HFF).

After 9 weeks, half of the HFF mice were treadmill exercise trained for 4 weeks (HFF+ExT), while the rest were kept sedentary. HFF resulted in increased body and liver weight, adiposity, hepatic steatosis and whole body glucose intolerance as well as decreased hepatic IRE1 phosphorylation.

Exercise training prevented the HFF-induced weight gain and partially prevented increased liver weight, adiposity and glucose intolerance, but with no effect on liver triglycerides. In addition, BiP protein and CHOP mRNA content increased with exercise training compared with CON and HFF, respectively.

Lack of PGC-1 in the liver only resulted in minor changes in the PERK pathway. In conclusion, this study provides evidence for dissociation between diet-induced hepatic triglyceride accumulation and hepatic UPR activation.

In addition, PGC-1 was not required for maintenance of basal UPR in the liver and due to only minor exercise training effects on UPR further studies are needed to conclude on the potential role of PGC-1 in exercise training-induced adaptations in hepatic UPR.