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Journal: Experimental physiology

164

Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl deficient mice have a lean and hypermetabolic phenotype with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS related phenotypes, we have now investigated the cardiovascular system. Gnasxl KO mice were ≈20 mmHg hypertensive compared to wild-type (WT) littermates (p≤0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate (HR) in conscious KOs (630±10 vs 584±12 bpm, KO vs WT, p≤0.05). Body temperature was also elevated (38.1±0.3 vs 36.9±0.4 °C, KO vs WT, p≤0.05). To investigate autonomic nervous system influences, we used heart rate variability (HRV) analyses. We empirically defined frequency power bands using atropine and reserpine and verified high frequency (HF) power and low frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. By contrast, atropine and exendin-4 (Ex-4), a centrally acting agonist of the glucagon-like peptide-1 (GLP-1) receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a stronger increase in HR in KOs. Mild stress had a blunted effect on LF/HF ratio in KOs consistent with elevated basic sympathetic activity. We conclude that XLαs is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues.

Concepts: Gene, Blood, Physiology, Acetylcholine, Autonomic nervous system, Sympathetic nervous system, Parasympathetic nervous system, Enteric nervous system

34

We have previously documented improvements in endothelium-dependent vasodilation with a Bikram (hot) yoga intervention in middle-aged adults. Presently, the effect of environmental temperature in hot yoga on endothelial function is unknown.

Concepts: Endothelium, Bikram Choudhury

31

Brown adipose tissue (BAT) has been implicated in the pathogenesis of obesity, type-2 diabetes and the metabolic syndrome, and is a potential therapeutic target. BAT can have a significant impact on energy balance and glucose homeostasis through the action of uncoupling protein (UCP)1, dissipating chemical energy as heat following neuro-endocrine stimulation. We hypothesised that psychological stress, which is known to promote cortisol secretion, would simultaneously activate BAT at thermoneutrality. BAT activity was measured using infrared thermography to determine changes in temperature of the skin overlying supraclavicular BAT (TSCR ). A mild psychological stress was induced in five healthy, lean, female, Caucasian volunteers using a short mental arithmetic (MA) test. TSCR was compared to a repeated assessment, where the MA test was substituted for a period of relaxation. Although MA did not elicit an acute stress response, anticipation of MA testing led to an increased in salivary cortisol, indicative of an anticipatory stress response, that was associated with a trend towards higher absolute and relative TSCR . A positive correlation between TSCR and cortisol was found during the anticipatory phase, a relationship that was enhanced by raised cortisol linked to MA. Our findings suggest that subtle changes in the level of psychological stress can stimulate BAT, findings that may account for the high variability and inconsistency in reported BAT prevalence and activity measured by other modalities. Consistent assessment of this uniquely metabolic tissue is fundamental to the discovery of potential therapeutic strategies against metabolic disease. This article is protected by copyright. All rights reserved.

Concepts: Anxiety, Nutrition, Energy, Diabetes mellitus, Obesity, Insulin resistance, Temperature, Metabolic syndrome

31

The perception of fatigue is common in many disease states, however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate, and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine if this combination could activate sensations, and if so determined how these subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30-s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis (APB). Infusion of individual metabolites at maximum amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4+300nM ATP+1mM lactate) also evoked no sensation. The infusion of a metabolite-combination found in muscle during moderate endurance-exercise (pH 7.3+400nM ATP+5 mM lactate) produced significant fatigue sensations. Infusion of a metabolite-combination associated with vigorous exercise (pH 7.2+500nM ATP+10mM lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischemic exercise) caused more ache but no additional fatigue-sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate, and ATP leads to fatigue-sensation and eventually pain, probably through activation of ASIC, P2X, and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

Concepts: Metabolism, Muscle, Sensory system, Muscular system, Acetylcholine, Muscle spindle, Peripheral neuropathy, Adductor pollicis muscle

29

It has been hypothesized that exercise-induced changes in metabolites and ions are crucial in the adaptation of contracting muscle. We tested this hypothesis by comparing adaptations to two different interval-training protocols (differing only in the rest duration between intervals), which provoked different perturbations in muscle metabolites and acid-base status. Prior to and immediately after training, 12 women performed the following tests: (1) a graded exercise test to determine peak oxygen uptake ( ); (2) a high-intensity exercise bout (followed 60 s later by a repeated-sprint-ability test; and (3) a repeat of the high-intensity exercise bout alone with muscle biopsies pre-exercise, immediately postexercise and after 60 s of recovery. Subjects performed 5 weeks (3 days per week) of training, with either a short (1 min; HIT-1) or a long rest period (3 min; HIT-3) between intervals; training intensity and volume were matched. Muscle [H(+)] (155 ± 15 versus 125 ± 8 nmol l(-1); P < 0.05) and muscle lactate content (84.2 ± 7.9 versus 46.9 ± 3.1 mmol (g wet weight)(-1)) were both higher after HIT-1, while muscle phosphocreatine (PCr) content (52.8 ± 8.3 versus 63.4 ± 9.8 mmol (g wet weight)(-1)) was lower. There were no significant differences between the two groups regarding the increases in , repeated-sprint performance or muscle Na(+),K(+)-ATPase content. Following training, both groups had a significant decrease in postexercise muscle [H(+)] and lactate content, but not postexercise ATP or PCr. Postexercise PCr resynthesis increased following both training methods. In conclusion, intense interval training results in marked improvements in muscle Na(+),K(+)-ATPase content, PCr resynthesis and . However, manipulation of the rest period during intense interval training did not affect these changes.

Concepts: Exercise, Following, English-language films, Lactic acid, High-intensity interval training, Interval training, Excess post-exercise oxygen consumption, Long slow distance

28

Lipopolysaccharide (LPS) can exacerbate asthma; however, the mechanisms are not fully understood. This study investigated the effect of LPS on antigen-stimulated mast cell degranulation and the underlying mechanisms. We found that LPS enhanced degranulation in RBL-2H3 cells and mouse peritoneal mast cells upon FcεRI activation, in a dose- and time-dependent manner. Parallel to the alteration of degranulation, LPS increased FcεRI-activated Ca(2+) mobilization, as well as Ca(2+) entry through store-operated calcium channels (SOCs) evoked by thapsigargin. Blocking Ca(2+) entry through SOCs completely abolished LPS enhancement of mast cell degranulation. Consistent with functional alteration of SOCs, LPS increased mRNA and protein levels of Orai1 and STIM1, two major subunits of SOCs, in a time-dependent manner. In addition, LPS increased the mRNA level of Toll-like receptor 4 (TLR4) in a time-dependent manner. Blocking TLR4 with Cli-095 inhibited LPS, increasing transcription and expression of SOC subunits. Concomitantly, the effect of LPS enhancement of Ca(2+) mobilization and mast cell degranulation was largely reduced by Cli-095. Administration of LPS (1 μg) in vivo aggravated airway hyperreactivity and inflammatory reactions in allergic asthmatic mice. Histamine levels in serum and bronchoalveolar lavage fluid were increased by LPS treatment. In addition, Ca(2+) mobilization was enhanced in peritoneal mast cells isolated from LPS-treated asthmatic mice. Taken together, these results imply that LPS enhances mast cell degranulation, which potentially contributes to LPS exacerbating allergic asthma. Lipopolysaccharide increases Ca(2+) entry through SOCs by upregulating transcription and expression of SOC subunits, mainly through interacting with TLR4 in mast cells, resulting in enhancement of mast cell degranulation upon antigen stimulation.

Concepts: Immune system, Inflammation, Asthma, Immunoglobulin E, Allergy, Mast cell, Histamine, Degranulation

27

The laryngeal chemoreflex (LCR), an airway protective reflex that causes apnea and bradycardia, has long been suspected as an initiating event in the sudden infant death syndrome (SIDS). Serotonin (5-HT) and 5-HT receptors may be deficient in the brainstems of babies who die of SIDS, and 5-HT seems to be important in terminating apneas directly or in causing arousals or as part of the process of autoresuscitation. We hypothesized that 5-HT in the brainstem would limit the duration of the LCR. We studied anesthetized rat pups between 7 and 21 days of age and made microinjections into the cisterna magna or into the nucleus of the solitary tract (NTS). Focal, bilateral microinjections of 5-HT into the caudal NTS significantly shortened the LCR. The 5-HT 1a receptor antagonist, WAY 100635, did not affect the LCR consistently, nor did a 5-HT2 receptor antagonist, ketanserin, alter the duration of the LCR. The 5-HT3 specific agonist, 1-(3-chlorophenyl)-biguanide, microinjected bilaterally into the caudal NTS significantly shortened the LCR. Thus, endogenous 5-HT released within the NTS may curtail the respiratory depression that is part of the LCR, and serotonergic shortening of the LCR may be attributed to activation of 5-HT3 receptors within the NTS. 5-HT3 receptors are expressed presynaptically on C-fiber afferents of the superior laryngeal nerve, and serotonergic shortening of the LCR may be mediated presynaptically by enhanced activation of inhibitory interneurons within the NTS that terminate during the LCR. This article is protected by copyright. All rights reserved.

Concepts: Receptor, Receptor antagonist, Serotonin, Agonist, Inverse agonist, Sudden infant death syndrome, 5-HT receptor, 5-HT2C receptor

25

Vagus nerve stimulation (VNS) has shown therapeutic potential for myocardial infarction-induced ventricular arrhythmias. This study aimed to investigate the effects of VNS on ventricular electrophysiological changes induced by hyper-sympathetic nerve activity. Seventeen open-chest dogs were subjected to left stellate ganglion stimulation (LSGS) for 4 h to simulate a hyper-sympathetic tone. All animals were randomly assigned to VNS group (n = 9) and control group (n = 8). In VNS group, VNS was performed at the voltage causing a 10% decrease of heart rate for hours 3-4 during 4-h of LSGS. During the first 2-h of LSGS, the ventricular effective refractory period (ERP) and action potential duration (APD) were both progressively and significantly decreased; the spatial dispersion of ERP, maximum slope of restitution curve, pacing cycle length of APD alternans were all increased. With LSGS+VNS during next 2 h, there was a significant return of all the changed electrophysiological parameters toward baseline levels. In 8 control dogs that received 4-h of LSGS without VNS, all the parameters were changed progressively but without any reversals. Ventricular fibrillation threshold was higher in VNS group than that in control group (17.3±3.4 V vs. 11.3±3.8 V, P<0.05). The present study demonstrated that VNS was able to reverse LSGS-induced ventricular electrophysiological changes and suppress the occurrence of ventricular fibrillation. This article is protected by copyright. All rights reserved.

Concepts: Action potential, Cardiac electrophysiology, Vagus nerve, Cranial nerves, Vagus nerve stimulation, Ventricular fibrillation, All rights reserved, Copyright

22

Manipulating rest-recovery interval between sets of resistance exercise may influence training-induced muscle remodeling. The aim of this study was to determine the acute muscle anabolic response to resistance exercise performed with short or long inter-set rest intervals.

Concepts: Metabolism, Cell biology, Muscle, Actin, Peptide synthesis, Acute accent, Renaissance music

19

What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in type II diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to type II diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-βI (PKC-βI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in type II diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-βI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC-βI. However, the junk-food diet also increased SGLT1 and SGLT2 levels at the proximal tubule BBM. Glucose reabsorption across the proximal tubule BBM, via GLUT2, SGLT1 and SGLT2, is not solely dependent on glycaemic status, but is also influenced by diet-induced changes in glucose metabolism. We conclude that different metabolic disturbances result in complex adaptations in renal glucose transporter protein levels and function.

Concepts: Nutrition, Insulin, Diabetes mellitus, Glucose, Obesity, Insulin resistance, Glucose transporter, Sodium-glucose transport proteins