bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of dietary fat and thyroid function on adipose conversion in male Sprague Dawley rats (1160.10)
Authors: Welch‐White Venus , Dawkins Norma , Graham Thomas , Bolden‐Tiller Olga
Published: June 2021

The thyroid hormones (THs) play critical roles in differentiation, growth and metabolism and are critical for the normal function of nearly all tissues, with major roles in regulating energy balance, metabolism of glucose, and lipids and metabolic rate. The two functionally different types of fat in mammals are: brown adipose tissue (BAT), containing specialized thermogenic brown adipocytes, and white adipose tissue (WAT), containing white adipocytes specialized in triglyceride metabolism. Both tissues are strongly involved in energy balance. The objective of this study was to evaluate and compare physiological and histological effects of saturated and unsaturated fats in periadrenal BAT and thyroid gland of euthyroid and thyroid altered rats. Adult male Sprague Dawley rats (n=100) were exposed to a control or one of four test diets; 25% and 27% (saturated or unsaturated) for 8 weeks. A chemically reduced thyroid state was obtained through the addition of .05% propylthioracil (PTU) in drinking water. The body weights of the normal animals were significantly higher than in the altered thyroid groups. Histopathological evaluations confirmed damage to thyroid tissue in the altered thyroid groups and revealed an increase in BAT to WAT conversion in the thyroid gland and periadrenal BAT. Gene expression of FABP and LXR was generally higher in thyroid altered animals compared to the euthyroid group. In conclusion, chemically induced hypothyroidism negatively impacted fat metabolism, which contributed to increased BAT to WAT conversion and increased expression of FABP and LXR.
The functional role of brown adipose tissue in whole‐body lipid metabolism in humans (1160.3)
Authors: Chondronikola Maria , Porter Craig , Hurren Nicholas , Chao Tony , Yfanti Christina , Labbé Sebastien , Annamalai Palam , Volpi Elena , Børsheim Elisabet , Sidossis Labros
Published: June 2021

Despite intense scientific interest regarding the role of human brown adipose tissue (BAT) in substrate metabolism, its role in whole‐body lipid metabolism remains unclear. To address this issue, we studied otherwise matched men with high (HBAT, n=7) and low (LBAT: n=5) BAT volume (69±18 mL vs. 4±2 mL, p<0.05) under cold exposure (CE) and thermoneutral (TN) conditions using positron emission tomography‐computed tomography, stable isotope infusions, and indirect calorimetry. For HBAT, but not LBAT participants, plasma free fatty acid concentrations (TN: 0.36±0.01mmol/L vs. CE: 0.63±0.01mmol/L, p<0.05), plasma glycerol concentrations (TN: 0.05±0.01 mmol/L vs. CE: 0.09±0.01 mmol/L, p<0.05), lipolysis (TN: 2.2±0.3 μmol/kg/min vs. CE: 5.9±0.6μmol/kg/min, p<0.05), and plasma free fatty acid oxidation (TN: 2.7±0.6 μmol/kg/min vs. CE: 5.9±1.0 μmol/kg/min, p<0.05) were higher under CE conditions than TN conditions. Moreover, during CE, plasma small LDL and large HDL particles increased more in the HBAT group than in the LBAT group (p<0.05). Finally, the HBAT group tended to have decreased plasma triglyceride concentrations the day after CE (‐33.4±11.4 mg/dl, p=0.06), whereas LBAT subjects showed no significant change. These novel findings demonstrate a functional role of BAT in human lipid metabolism.

Grant Funding Source: : CTSA UL1TR000071, Pepper Center Pilot Grant, Sealy Center on Aging, Shriners Hospitals
The developmental transition of epicardial, paracardial and omental adipose tissue during early life in the sheep (1160.7)
Authors: Davies Graeme , Birtwistle Mark , Pope Mark , Perry Vivienne , Sacks Harold , Budge Helen , Symonds Michael
Published: June 2021

Study objective: This study focused on the transition of epicardial, paracardial and omental fat during early postnatal life using analysis of gene expression.

Methods: Sheep were euthanased for adipose tissue sampling at 1, 7 and 28 days of age (n=4 per time point) under UK Home Office Approval. Paracardial adipose tissue was sampled at all ages, whereas epicardial and omental adipose tissues were only present at 7 and 28 days. RNA was extracted and gene expression analysed by qRT‐PCR. Data was analysed using one‐way ANOVA or unpaired t‐Test.

Results: With increasing age, the white fat markers leptin and RIP140 mRNA expression increased in all depots studied. PPAR gamma, involved in adipocyte differentiation, also increased with age. Conversely, uncoupling protein (UCP)1 mRNA abundance decreased with age. Putative mRNA markers of brown (lhx8) and beige (tmem26) adipose tissue in rodents were below the limits of detection in all fat depots studied.

Conclusions: This study suggests a brown to white fat transformation with increased adipocyte differentiation in all depots studied, irrespective of a fetal (e.g. paracardial) or postnatal (e.g. omental) origin.
Acute lysine supplementation does not improve hepatic or peripheral insulin sensitivity in older, obese individuals (1161.7)
Authors: Kim Il‐Young , Bodenner Donald , Wolfe Robert , Coker Robert
Published: June 2021

Context: Lysine supplementation may have a positive influence on the regulation of glucose metabolism but it has not been evaluated in older individuals.

Objective: We evaluated the impact of acute lysine supplementation using three randomized experimental scenarios: 1) oral glucose alone (control), 2) oral glucose and low‐dose lysine (2 g), and oral glucose and high dose lysine (5 g) lysine in 7 older (66±1 years/age), overweight (BMI = 31±2 kg/m2) individuals.

Methods: We utilized a dual tracer technique (ie., [1‐13C] glucose oral ingestion and [6,6‐2H2] glucose infusion) during an oral glucose tolerance test (OGTT) to examine differences in hepatic and peripheral insulin sensitivity under all three scenarios.

Results: Plasma glucose and insulin data were not different between the control, 2 g lysine and 5 g of lysine trials. The results of the Matsuda index were also not different between the three trials. As an index of hepatic insulin sensitivity, there were no significant differences in the endogenous glucose rate of appearance (glucose Ra) for control, 2 g lysine and 5 g lysine (1.2±0.1, 1.1±0.1, 1.3±0.1 mg•kg‐1•min‐1), respectively. With respect to peripheral insulin sensitivity, there were no significant differences in the glucose rate of disappearance (glucose Rd) for control, 2 g lysine and 5 g lysine (4.2±0.2, 4.3±0.2, and 4.5±0.4 mg•kg‐1•min‐1), respectively.

Conclusions: Previous studies in younger participants have suggested that lysine may have a beneficial effect on glucose metabolism. Unfortunately, acute lysine supplementation in the older population does not facilitate beneficial changes in glucose Ra or glucose Rd.

Grant Funding Source: NIH grants 1P30AG028718‐01A2; UL1TR000039 and KL2TR000063
Heat stress treatment completely rescues denervation‐induced reduction of mitochondrial enzyme activity in skeletal muscle (1162.10)
Authors: Tamura Yuki , Matsunaga Yutaka , Kitaoka Yu , Hoshino Daisuke , Hatta Hideo
Published: June 2021

Contrary to exercise training, physical inactivity decreases mitochondrial content and oxidative capacity in skeletal muscle, which contributes to muscle atrophy and dysfunction. In this study, we examined whether heat stress treatment effectively counters disuse‐induced negative adaptations of mitochondria in skeletal muscle. As a result, maximal citrate synthase (CS) activity, a biomarker of mitochondrial content, and 3‐hydroxyacyl CoA dehydrogenase (3‐HAD), a biomarker of maximal capacity for beta oxidation, in gastrocnemius muscle of ICR mice were significantly decreased following 10 days of experimental physical inactivity, produced by unilateral sciatic nerve transection (CS: ‐33.8% P<0.01, 3‐HAD: ‐38.3% P<0.001, vs sham‐operated limb without heat stress). However, daily heat stress treatment, produced by exposure of mice to a hot environment (40 °C, 30 min/day), completely rescued denervation‐induced reduction of CS and 3‐HAD activities (CS: ‐ 5.1% P=0.90, 3‐HAD: +2.9% P=0.96, vs sham‐operated limb without heat stress). Our current observations show that heat stress treatment appears to be clinically beneficial for people who have difficulty participating in sufficient exercise training such as the elderly, injured athletes, and patients with nerve damage.
Effects of diet on muscle strength, mitochondria function, and metabolic parameters of old rats (1162.6)
Authors: Lin Shang‐ying , Chen Chiao‐nan
Published: June 2021

Loss of muscle mass and strength (sarcopenia) is a phenomenon that occurs in the elderly. Many studies have found that sarcopenia is related to the decreased function of mitochondria. Additionaly mitochondrial function is known affected by metabolic characteristics of animals. The purpose of this study was to examine the effects of diet on muscle strength, mitochondrial function and metabolic parameters in old rats. Sixteen month‐old rats were randomized into ad libitum (AL), calorie restriction (CR) or high fat diet (HFD) groups and received 14‐weeks of diet intervention. Grip strength, glucose tolerance, and the levels of insulin, free fatty acid (FFA) and triglyceride (TG) were determined by the end of intervention. Soleus muscles were used for the mitochondrial function assay. Our results showed that rats with CR had better normalized grip strength compared with rats with AL and HFD. Accordingly, rats with CR had better mitochondrial function and metabolic characteristics than rats with AL and HFD. Rats with CR had better glucose tolerance than the HFD group, which showed insulin resistance after the intervention. Besides, CR group had lower FFA compared with AL and HFD groups, and lower TG compared with the HFD group. In summary, CR is beneficial to muscle strength, mitochondrial function and metabolic parameters in old rats.
A maternal high fat diet has long‐lasting effects on skeletal muscle lipid and PLIN protein content in rat offspring at young adulthood (1162.7)
Authors: MacPherson Rebecca , Castelli Laura , Miotto Paula , Frendo‐Cumbo Scott , Milburn Amanda , Roy Brian , LeBlanc Paula , Ward Wendy , Peters Sandra
Published: June 2021

High fat diets (HFD) can have adverse effects on skeletal muscle development. Skeletal muscle PLIN proteins (PLIN2, 3, & 5) are thought to play critical roles in lipid metabolism, however effects of HFD on PLINs as well as lipases (HSL, ATGL, CGI‐58) have yet to be investigated. The objective of this study was to determine whether HFD would influence skeletal muscle lipase and PLIN protein content in dams as well as offspring at weaning (19d) and young adulthood (3mo). Female rats (28d old, n=9/group) were fed control (CON, AIN93G, 7% soybean oil) or HFD (AIN93G, 20% lard) for 10wks prior to mating, throughout pregnancy and lactation. Offspring were weaned onto CON (n=18/group, one female & one male pup per litter was studied at 19d & 3mo of age). Because there was no effect of sex for outcomes measured, male and female data was combined. HFD resulted in increased lipid content in plantaris of dams and pups, both at weaning and at 3mo (p=0.07). HFD resulted in increased PLIN3 content in plantaris of dams (P=0.016) and increased PLIN5 content in pups at weaning and 3mo (p=0.05). PLIN2 and PLIN5 content increased at 3mo vs. weaning (P<0.001). Diet had no effect on ATGL, CGI‐58, or HSL content. The data suggest that exposure to a maternal HFD results in increased skeletal muscle lipid and PLIN5 content in offspring through to young adulthood. Funded by NSERC.
Exercise training prevents myocardial infarction induced‐skeletal muscle atrophy by reducing oxidative stress in rats (1163.6)
Authors: Cunha Telma , Bechara Luiz , Bacurau Aline , Fernandes Tiago , Scavoni Cristoforo , Gabriel Daniele , Ferreira Julio , Brum Patricia
Published: June 2021

Heart failure (HF) is a syndrome that compromises not only cardiovascular system, but other tissues, such as skeletal muscle. Skeletal muscle atrophy (SMA) is an independent predictor of mortality and oxidative stress is one of factors related to this atrophy. The objective of this study was to evaluate the role of oxidative stress in SMA induced by HF and the effect of aerobic exercise training (AET) in modulating this mechanism. Male rats were randomly assigned into groups: myocardial infarction (MI) and fictitious surgery (SHAM). These groups were submitted or not to 8 weeks of AET (1h running sessions at 60%VO2max) and were named sedentary or trained (MI‐SED; MI‐T; SHAM‐SED; SHAM‐T). All the values were presented as mean ± SE. To compare results, two‐way ANOVA was applied with Duncan pos hoc when necessary (p<0.05). The MI‐SED rats presented reduced plantaris cross‐sectional and AET prevented this atrophy and improved exercise tolerance in MI‐T. MI induced oxidative stress and AET attenuated oxidative stress biomarkers. Serum TNF‐α was elevated in MI‐SED and AET restored the MI values to SHAM‐SED levels (SHAM‐SED: 3.8 ± 0.5 vs. MI‐SED: 6.2 ± 28 vs. MI‐T: 3.2 ± 0.4 pg/µg). NF‐kB activity, which is a proteolysis marker, was reduced in MI‐T when compared to MI‐SED (MI‐T: 16228.3 ± 1621.5 vs. MI‐SED 20870.7 ± 927.8 A.U.). p38 MAPK levels were elevated after MI with no impact of AET on that levels (SHAM‐SED: 1.0 ± 0.21 vs. MI‐SED: 2.74 ± 0.26 vs. MI‐T: 1.6± 0.24 A.U.). Taking together these data provide evidence for oxidative stress associated with HF‐induced SMA and AET prevented atrophy by reducing oxidative stress and NF‐kB signaling pathway in MI rats.

Grant Funding Source: FAPESP
Effects of leucine and HMB supplementation under proteasome pathways during different sarcopenic conditions (1163.9)
Authors: Baptista Igor , Silva Willian , Silvestre João , Moriscot Anselmo
Published: June 2021

In this study we have compared the effects of leucine supplementation and its metabolite β‐Hydroxy‐β‐Methyl‐Butyrate (HMB) on the ubiquitin‐proteasome system pathway during two distinct atrophic conditions, hindlimb immobilization and dexamethasone treatment. Leucine supplementation was able to minimize the reduction in rat soleus mass and cross sectional area (CSA) driven by immobilization, but not during dexamethasone treatment. Interestingly, HMB supplementation was unable to provide protection against mass loss or CSA in all treatments. While leucine supplementation was able to minimize increased expression of both Atrogin and MuRF1 in immobilized rats, leucine was only able to minimize Atrogin in dexamethasone treated rats. In contrast, HMB was unable to restrain the increase in those atrogenes in immobilized rats, but in dexamethasone treated rats, HMB minimized gene expression of Atrogin. Leucine supplementation maintained soleus tetanic peak force in immobilized rats at normal level; differently, HMB treatment failed to maintain tetanic peak force. The present data suggested that the anti‐atrophic effects of leucine are not mediated by its metabolite HMB.
Study of a multiprotein complex involved in excitation‐transcription coupling in skeletal cells (1164.9)
Authors: Arias‐Calderón Manuel , Almarza Gonzalo , Contreras‐Ferrat Ariel , Jaimovich Enrique , Buvinic Sonja
Published: June 2021

Pannexin‐1 (Panx1) releases ATP to the extracellular space in skeletal muscle cells in response to electrical stimulation. ATP is a relevant mediator between membrane depolarization and gene expression. We propose that this signaling pathway would require the proper coordination between the voltage sensor (dihydropyridine receptor, DHPR), pannexin1 channels (PnX1, ATP release conduit), nucleotide receptors, and several signaling molecules. The goal of this study was to assess protein‐protein interactions within the E‐T machinery in several models. Newborn derived myotubes, adult fibers, triad fractions from rat or mouse skeletal muscles and L6 cells overexpressing PnX1 have been used. In all the models co‐immunoprecipitation between DHPR, PnX1, P2Y2 receptor and dystrophin has been detected. Using 2D blue‐native SDS/PAGE we detected that DHPR, PnX1, P2Y2, caveolin3 and dystrophin belong to the same multiprotein complex. Using the proximity ligation assay associated to confocal microscopy, we observed co‐localization between DHPR, PnX1, P2Y2 and caveolin3.

Unveiling the molecular actors involved in the regulation of gene expression could contribute to the understanding and treatment of skeletal muscle disorders such as muscular dystrophies and sarcopenia associated with aging.

Grant Funding Source: Supported by Fondecyt‐1110467‐11100454, Conicyt‐79090021, FONDAP‐15010006, ACT‐1111
Progressive vasoconstrictory sympathetic outflow via muscle metaboreflex activation gradually increases human arterial stiffness (1165.4)
Authors: Prodel Eliza , Fernandes Igor , Barbosa Thales , Hawerroth Pedro , Nobrega Antonio Claudio , Vianna Lauro
Published: June 2021

Previous studies demonstrated that stepped intravenous infusion of noradrenaline increases aortic and peripheral arterial stiffness. However it is unknown whether these findings could be extended to physiological stimulation. Given this, we tested the hypothesis that a graded vasoconstrictory sympathetic outflow via skeletal muscle metaboreflex activation would gradually increase human aortic arterial stiffness (AIx). In nine healthy male subjects (22±2 yr), the graded isolation of the muscle metaboreflex was achieved by post‐exercise ischemia (PEI) following moderate and high intensity static handgrip performed at 30% and 40% maximum voluntary contraction, in a counterbalanced order. Heart rate (ECG), mean arterial pressure (MAP), Alx (SphygmoCor) and radial artery diameter (Doppler) were measured. MAP increased significantly from rest during PEI30% (105±4 mmHg vs 83±2 mmHg; P<0.05) and was a further augmented during PEI40% (115±3 mmHg vs PEI30%; P<0.05), indicating graded metaboreflex activation. Similarly, Alx increased significantly from rest during PEI30% (Rest ‐9±3% vs PEI30% 9±5%, P<0.05) and was further augmented during PEI40% (17±4% vs PEI30%; P<0.05). Radial artery diameter was unchanged throughout. The present results extend previous findings from pharmacological studies by showing that progressive muscle metaboreflex activation gradually increases human arterial stiffness.

Grant Funding Source: Supported by CAPES, CNPq, FAPERJ, FINEP
Purinergic 2X receptors play a role in evoking the exercise pressor reflex in rats with peripheral artery insufficiency (1165.6)
Authors: Stone Audrey , Yamauchi Katsuya , Kaufman Marc
Published: June 2021

Purinergic 2X (P2X) receptors on the endings of thin fiber afferents have been shown to play a role in evoking the exercise pressor reflex in cats. In this study, we attempted to extend this finding to decerebrated, unanesthetized rats whose femoral arteries were either freely perfused or were ligated 72 hours before the start of the experiment. We first established that our dose of PPADS (10 mg/ kg), a P2X receptor antagonist, attenuated the pressor response to α, β methylene ATP (10 µg/ kg), a P2X receptor agonist. We then compared the exercise pressor reflex before and after infusing PPADS into the arterial supply of the hind limb muscles that were statically contracted. In rats with freely perfused femoral arteries, the peak pressor responses to contraction were not significantly attenuated by PPADS (before PPADS: 19±2mmHg, 13 min after PPADS: 17±2mmHg, and 25 min after PPADS: 17±3mmHg). Likewise, the cardioaccelerator and renal sympathetic nerve responses were not significantly attenuated. In contrast, we found that in rats whose femoral arteries were ligated, PPADS significantly attenuated the peak pressor responses to contraction (before PPADS: 37±5mmHg, 13 min after PPADS: 27±6mmHg, 25 min after PPADS: 25±5mmHg; p<0.05). Heart rate was not significantly attenuated, but renal SNA was at certain time points over the 30s contraction period. We conclude that P2X receptors play a role in evoking the exercise pressor reflex in rats whose femoral arteries were ligated, but do not play a role in evoking the reflex in rats whose femoral arteries were freely perfused.

Grant Funding Source: Supported by NIH grants HL‐096570 and AR‐059397
Lipid‐induced insulin resistance is associated with impaired muscle protein synthetic response to amino acid ingestion in healthy young men (1168.2)
Authors: Stephens Francis , Chee Carolyn , Wall Benjamin , Murton Andrew , van Loon Luc , Tsintzas Kostas
Published: June 2021

The ability to maintain skeletal muscle mass appears to be impaired in insulin resistant conditions. The present study investigated the effect of lipid induced insulin resistance on the rate of muscle protein synthesis. Seven healthy male volunteers (23 ± 1 y, 24 ± 1 kg/m2) underwent a 7 h intravenous infusion of [ring‐2H5]phenylalanine (0.5 mg/kg/h) on two randomised occasions combined with either 0.9% saline or 10% Intralipid (100 mL/h; Fresenius Kabi, Germany). After a 4 h ‘basal’ period, a 21 g bolus of amino acids (except phenylalanine and tyrosine) was administered in a 440 mL solution nasogastrically, and a 3 h euglycaemic (4.5 mmol/L) hyperinsulinemic (50 mU/m2/min) clamp was commenced (‘fed’ period). Muscle biopsies were obtained from the vastus lateralis at 1.5, 4, and 7 h. Lipid infusion resulted in elevated levels of plasma free fatty acids when compared to saline (P<0.001), which reduced fed glucose disposal by 20% (P<0.01) and pyruvate dehydrogenase complex activation by 50% (P<0.05). Furthermore, whereas mixed muscle fractional synthetic rate increased from the basal to fed period during saline infusion (0.040 ± 0.010 to 0.067 ± 0.013 %/h; P<0.05), it did not respond during lipid infusion (0.048 ± 0.013 to 0.038 ± 0.005 %/h), despite the same circulating insulin and leucine concentrations. Thus, lipid induced insulin resistance results in anabolic resistance to amino acid ingestion in healthy young men.
Hyperaminoacidemia eliminates the influence of body fat and insulin sensitivity on fractional synthesis rate and myostatin regulation in humans (1168.3)
Authors: Tran Lee , Masters Haley , Katsanos Christos
Published: June 2021

Multiple conditions are linked to perturbed skeletal muscle protein (SMP) metabolism, including excess adiposity and insulin resistance. Here we delineate the precise roles of body fat and insulin sensitivity on SMP metabolism, and test the hypothesis that hyperaminoacidemia can eliminate the influence of these factors. Six healthy individuals underwent a DEXA scan to determine percent body fat (%BF; 16.3‐29.4%) and an oral glucose tolerance test (OGTT) to evaluate insulin sensitivity via Matsuda index (MI; 1.21‐12.0). Subjects received a primed, continuous infusion of L‐[2,3,3,4,5,5,5,6,6,6‐2H10]leucine to determine SMP fractional synthesis rate (FSR) in biopsies from the vastus lateralis. Myostatin (MSTN) mRNA, a marker of muscle wasting, was quantified in similar biopsies, and MSTN activation was assessed in plasma as the percent of active over latent protein. To evaluate the effect of hyperaminoacidemia, samples were collected before and during infusions of high amino acids (AA). In our subjects, %BF was not correlated with MI (P=0.11). The %BF was only associated with MSTN mRNA (P=0.02; r=0.81). However, MI was a key determinant in FSR (P=0.02; r=0.83) and MSTN activation (P<0.01; r=‐0.94). AA infusion eliminated all discrepancies in FSR and MSTN quantitations. Thus, SMP metabolism is more strongly linked to insulin sensitivity than body fat, but the influence is attenuated with hyperaminoacidemia.

Grant Funding Source: Supported by NIH/NIDDK Grant# R01 DK094062; NCATS Grant# UL1 TR000135
Angiotensin II‐induced inhibition of sodium currents in aortic baroreceptor neurons mediates blunted arterial baroreflex sensitivity in heart failure rats (1169.3)
Authors: Liu Jinxu , Zhang Dongze , Zheng Hong , Muelleman Robert , Li Yu‐Long
Published: June 2021

Impairment of arterial baroreflex sensitivity (ABS) is associated with increased mortality in patients with chronic heart failure (CHF). Increase in plasma angiotensin II (Ang II) level is often seen in CHF and contributes to the baroreflex dysfunction. Our previous studies have confirmed that reduced expression of voltage‐gated sodium (Nav) channels in aortic baroreceptor (AB) neurons is involved in attenuation of the ABS in CHF rats. In this study, we investigated acute effect of Ang II on Nav currents in AB neurons and on the ABS from sham and CHF rats. Using Ang II 125I radioimmunoassay, real‐time PCR and western blot, we found that Ang II level, mRNA and protein expression of Ang II type 1 (AT1) receptor in nodose ganglia (NG) from CHF rats were higher than that from sham rats. Data from whole cell patch‐clamp recording showed that Ang II (100 nM) acutely inhibited Nav currents in A‐ and C‐type AB neurons from sham and CHF rats. AT1 receptor antagonist losartan (1 µM) totally abolished the effect of Ang II on Nav currents. In addition, the inhibitory effect of Ang II on Nav currents was larger in CHF rats than that in sham rats. Local microinjection of Ang II (0.2 nmol) into the NG decreased the ABS in sham rats. However, local losartan (1 nmol) improved the blunted ABS in CHF rats. These results suggest that elevated endogenous Ang II in the NG contributes to the impaired ABS in CHF rats through inhibiting Nav channels.

Grant Funding Source: Supported by National Heart, Lung, and Blood Institute grant HL‐098503 (to Y.‐L.L.)
Baroreflex sensitivity during intestinal ischemia (1169.6)
Authors: Aletti Federico , Gambarotta Nicolò , Penn Alexander , Baselli Giuseppe , Schmid‐Schönbein Geert , Ferrario Manuela
Published: June 2021

Autonomic control of heart rate (HR) during prolonged intestinal ischemia was investigated by mathematical analysis of cardiac baroreflex. 24 Wistar rats underwent splanchnic arterial occlusion (SAO) under anesthesia and received different treatments, which included enteral saline or glucose, intramuscular xylazine and i.v. glycopyrrolate. High fidelity continuous arterial blood pressure (ABP) was measured by a catheter placed in the femoral artery. Time series of systolic blood pressure (SBP) and heart period (HP) were derived from the continuous ABP. Baroreflex gain (from SBP to HP) was calculated both in the low frequency (LF, 0.25‐0.75 Hz) and high frequency (HF, 0.75‐2.5 Hz) spectral bands. After a variable delay, ABP began to steadily decrease until either sacrifice at 4 hours after SAO or collapse by a sudden, fast fatal drop (FFD) of ABP. FFD was prevented by treatment with glycopyrrolate. Rats who displayed the FFD had a higher LF gain in the period (~ 5 mins) preceding the FFD with respect to the post‐SAO period (0.22 ± 0.11 ms/mmHg vs. 0.36 ± 0.15 ms/mmHg, p‐value < 0.05). These preliminary results suggest a sympathetic hyperactivation in the FFD rats and hint that the sympathetic system reaches saturation before the FFD, with the possibility of a sudden shift of the sympatho‐vagal balance towards a parasympathetic driven control of HR.

Grant Funding Source: Supported by the ShockOmics project of the European Union (Grant#602706)
Statin therapy decreases cardiac sympathetic activity in patients with left ventricular dysfunction: a 123l‐MIBG myocardial scintigraphy study (1169.9)
Authors: Fernandes Igor , Vianna Lauro , Freitas Raphael , Miranda Sandra , Mesquita Evandro , da Nóbrega Antonio , Mesquita Claudio
Published: June 2021

Convincing animal and human studies indicate that statin therapy decreases renal and muscle sympathetic nerve activity. Reduced cardiac sympathetic drive and innervation have also been reported as pleiotropic consequences of statin therapy in a rat coronary ligation model. This study then investigated whether these results could be translated to a clinical setting of human left ventricular dysfunction. Washout rate (WR) and heart‐to‐mediastinum (H/M) ratio, indexes of cardiac sympathetic activity and innervation density, were obtained from planar 123l‐metaiodobenzylguanidine myocardial scintigraphy images of patients undergoing long‐term statin [30±7 mg/day for at least a month] (7 men and 4 women, NYHA class II‐III, ejection fraction of 45±5%, age of 53±4, and body mass of 83±5 kg) and only standard drug therapy (7 men and 6 women, NYHA class II‐III, ejection fraction of 37±7%, age of 57±2 years, and body mass of 77±7 kg). Resting cardiovascular variables and lipid profiles were similar between groups. Statin users presented lower WR (Statin 29±2% vs. SDT 39±1, P<0.05) whereas early (1.7±0.2 vs. 1.6±0.2, P>0.05) and late (Statin 1.6±0.2 vs. SDT 1.6±0.4, P>0.05) H/M were similar for both groups. Our findings partially extend the results of animal studies and indicate that statin therapy reduces cardiac sympathetic activity in patients with left ventricular dysfunction without changing innervation density.

Grant Funding Source: Supported by CAPES, CNPq, FAPERJ, FINEP.
Health benefits of wholegrain ő a systematic review of the evidence to propose a daily intake recommendation (117.1)
Authors: Chanson‐Rollé Aurélie , Lappi Jenni , Meynier Alexandra , Poutanen Kaisa , Vinoy Sophie , Braesco Véronique
Published: June 2021

Objectives: Recommendations on wholegrain (WG) consumption are widespread but rarely quantitative. This work attempted to systematically review published human studies to quantify the daily intake of WG associated to favourable health outcomes. Results related to cardiovascular diseases (CVD) and type‐2 diabetes (T2D) are presented here.

Methods: Databases were searched from 1993 to 2012. Retrieved papers were screened by 3 PhDs. Six articles were selected for each outcome. A meta‐analysis was done using multivariate‐adjusted risk ratios of CVD comparing highest and lowest WG intake levels. Then, meta‐regressions were performed on CVD and T2D rates relative to WG amounts by using a hierarchical mixed linear model.

Results: First, we confirmed a significant inverse association between WG intake and CVD risk (overall RR = 0.84; p=0.004). Although quantitative meta‐regression failed to demonstrate a significant relationship between WG intake and CVD rate, a significant relationship was observed for T2D (p<0.0001), with an overall reduction of 0.03% in T2D incidence for each additional g of WG consumed daily.Conclusion: A significant association was observed between WG intake and T2D occurrence. Consuming 45 g/d of WG ingredients would decrease T2D risk by 21% as compared to consuming 7.5 g/d. This amount of WG, in line with current recommendations in North America, should be considered for recommendations.
Effects of dairy vs. sugar‐sweetened products on insulin sensitivity, pancreatic β‐cell function and plasma lipids in men and women at risk for type 2 diabetes mellitus (117.3)
Authors: Maki Kevin , Nieman Kristin , Schild Arianne , Kaden Valerie , Lawless Andrea , Kelley Kathleen , Rains Tia
Published: June 2021

This randomized, controlled, crossover trial assessed the effects of dairy (2 servings/d 2% milk and 1 serving/d low‐fat yogurt) vs. sugar‐sweetened (2 servings/d non‐diet soda and 1 serving/d non‐dairy pudding) product consumption for 3 wk on insulin sensitivity, β‐cell function, and plasma lipids. Subjects were 34 consumers of sugar‐sweetened beverages (蠅2 servings/d), 50% female, mean age 53.8 y and BMI 32.2 kg/m2, with multiple risk factors for type 2 diabetes mellitus (T2DM). A liquid meal tolerance test (LMTT) was administered at baseline (BL) and the end of each treatment. Changes from BL (dairy condition shown first) were significantly different between conditions for mean homeostasis model assessment insulin sensitivity (HOMA‐%S; 17.8 vs. ‐17.3%; P = 0.01; BL = 127.1%), LMTT disposition index (‐0.03 vs. ‐0.36; P = 0.01; BL = 2.59), and HDL‐C (0.8 vs. ‐4.2%; P = 0.01; BL = 44.3 mg/dL). Median changes from BL in LMTT Matsuda insulin sensitivity index (0.54 vs. ‐0.26; BL = 4.16) and HOMA β‐cell function (0.5 vs. 3.8%; BL = 68.4%) did not differ significantly between treatments. These results suggest that dairy consumption, compared with sugar‐sweetened products, improves HOMA‐%S, LMTT disposition index, and HDL‐C in men and women at‐risk for T2DM.

Grant Funding Source: Dairy Research Institute
Risk factor modification in pre‐diabetic adults consuming white button mushrooms rich in the anti‐oxidant, ergothioneine (117.4)
Authors: Calvo Mona , Beelman Robert , Mehrotra Anita , Nadkarni Girish , Wang Lingzhi , Boon Cher Goh , Uribarri Jaime
Published: June 2021

Oxidative stress & vitamin D (vitD) deficiency increase reactive oxygen species & low‐grade inflammation contributing to type 2 diabetes (T2D). To determine the effects of nutrition intervention with an antioxidant from WBM on T2D risk, we conducted 20 analyses of results from a study of health effects of vitD‐enriched‐WBM in pre‐diabetics. Group vitD intakes varied, but had no influence on oxidative risk factors. All of the 37 pre‐diabetic subjects consumed 100g WBM/d for 4 m in this study, enabling us to assess changes from baseline of risk factors associated with ergothioneine (ergo) antioxidant intake from WBM. As shown below, we used paired‐t‐tests to assess significant change from baseline for serum ergo & biomarkers of risk at 4 m (P1), and at 5 m (P2) [1m after diet ended]. Early analyses show significant (P<0.01) decreases from baseline of pro‐oxidant, advanced glycation end products with WBM‐ergo intake. Significant increases from baseline occurred for serum ergo, adiponectin & ORAC, at 4 & at 5 m, for all but ORAC. We conclude WBM are bioavailable food sources for the antioxidant ergo in older pre‐diabetic adults & their consumption effectively modifies risk factors for T2D.

Changes of biomarkers during the study

Biomarker
Baseline
4 months
5 months
p1
p2

Isoprostane
178±88
166±72
176±79
.38
.71

Leptin
24.3±14.3
24.9±15.6
24±14
.95
.98

Adiponectin
7.9±3.2
8.8±3.5
9.5±4.3
.02
.02

ORAC
5570±1683
6088±1696
5740±1523
.02
.70

Ergothioneine
317±163
677±497
496±340
.01
.01
Reducing circulating levels of plant sterols by ezetimibe favorably increases platelet counts in sitosterolemia patients (117.7)
Authors: Othman Rgia , Myrie Semone , Mymin David , Merkens Louise , Roullet Jean‐Baptiste , Steiner Robert , Jones Peter
Published: June 2021

Macrothrombocytopenia and hemolytic anemia is correlated with increased plant sterol (PS) levels in patients (pts) with sitosterolemia (STSL). To determine if ezetimibe (EZ), a sterol‐absorption inhibitor, improves platelet count and morphology, and reduces markers of red blood cell hemolysis (RBCH: serum lactate dehydrogenase and bilirubin), 8 STSL pts were first taken off their EZ therapy for 14 wks then treated with EZ (10 mg/d) for another 14 wks. Blood samples were collected at the end of each study phase (off and on EZ). Plasma (pl) and RBC sterol concentrations were analysed by gas chromatography. Complete blood cell count and serum RBCH markers were determined by automated analyzers. In pts off EZ, platelet count was inversely related to pl campesterol (r=‐0.85, p<0.05), total PS (r=‐0.77, p<0.05) and total PS‐to‐cholesterol ratio (PS/Chol, r=‐0.96, p<0.01, n=7). Platelet size was positively correlated with pl total PS and PS/Chol ratio (all r=0.93, p<0.05, n=5), and RBC PS and PS/Chol were inversely related to mean corpuscular hemoglobin (Hb) concentration (MCHC) (p<0.01). EZ reduced pl and RBC sitosterol (‐35±4 and ‐28±3%), campesterol (‐47±4 and ‐40±4%), total PS (‐37±4 and ‐28±3%, all p<0.0001) and PS/Chol (‐27±4 and ‐28±4%, p<0.01). EZ increased platelet count (+23±9%, p<0.05), decreased platelet size (‐10±3%, p<0.05), and had no effect on RBCH, RBC mean corpuscular volume, or Hb concentration but slightly increased (p=0.03) MCHC. MCHC was negatively correlated with RBC (r=‐0.76) and pl (r=‐0.85, all p<0.05) campesterol in pts on EZ. In pts off EZ, RBC Chol was inversely related to sitosterol (p<0.05), total PS (p<0.05) and PS/Chol (p<0.01), suggesting reciprocity between Chol and PS. EZ tended to lower pl Chol concentrations (‐12±6%, p=0.09) but not RBC Chol (+0.3±3%, NS). These results indicated that EZ reduced pl and RBC PS contents, increased platelet count and decreased platelet size without affecting RBC Chol levels in STSL pts.

Grant Funding Source: NIH, CIHR
Neurovascular control following small muscle mass exercise in humans (1170.10)
Authors: Buck Tahisha , Romero Steven , Ely Matt , Sieck Dylan , Abdala Pedro , Halliwill John
Published: June 2021

Sympathetic vascular transduction is blunted and the arterial baroreflex curve is reset to a lower operating pressure after dynamic large muscle mass exercise in humans. It is unknown whether these neural adaptations contribute to sustained post‐exercise vasodilation in small muscle mass exercise. The purpose of this study was to determine if cardiovagal, vascular, and integrated baroreflex sensitivity as well as sympathetic neurovascular transduction were altered following dynamic knee extension (DKE) exercise. It was hypothesized that sympathetic vascular transduction would be reduced after DKE, the arterial baroreflex would be reset to a lower operating point, and baroreflex sensitivity would be enhanced. Eleven healthy, college‐aged subjects completed one‐leg DKE exercise for one hour at 60% of peak power. Neurovascular transduction was estimated by measuring the percent change in femoral vascular conductance due to external neck pressure. There was no effect of exercise on transduction (P = 0.46) and no difference in integrated baroreflex sensitivity across time (P = 0.77). Cardiovagal baroreflex sensitivity increased 25% relative to baseline and had not recovered at 60 minutes post‐exercise (P = 0.02). Vascular baroreflex sensitivity was reduced in both the exercised (P = 0.05) and rested leg (P = 0.09). There is likely no effect of small muscle mass exercise on postexercise sympathetic transduction, the carotid baroreflex, or integrated baroreflex sensitivity. Cardiovagal baroreflex sensitivity was augmented and vascular baroreflex sensitivity was reduced after exercise and this has not been previously shown after small muscle mass exercise.

Grant Funding Source: NIH R01 HL115027
Activation of KIR channels and Na+/K+‐ATPase is not obligatory to blunt sympathetic vasoconstriction in contracting human skeletal muscle (1170.6)
Authors: Crecelius Anne , Luckasen Gary , Larson Dennis , Dinenno Frank
Published: June 2021

Activation of inwardly‐rectifying potassium (KIR) channels and Na+/K+‐ATPase regulates muscle blood flow during mild exercise; whether these pathways are involved in the blunting of sympathetic α‐adrenergic vasoconstriction in active muscle is unknown. We tested the hypothesis that α1‐adrenergic vasoconstriction (phenylephrine; PE) is augmented during exercise after inhibition of KIR channels and Na+/K+‐ATPase. Young adults (n=11) were instrumented with a brachial artery catheter (drug infusions and blood pressure) and forearm blood flow (Doppler ultrasound) was measured and vascular conductance (FVC) calculated at rest, during minute 4 of steady‐state hyperemic conditions (moderate handgrip exercise or adenosine; ADO), and after 2 min of PE in these conditions: control (saline), combined inhibition of nitric oxide (NO; L‐NMMA) and prostaglandins (PGs; ketorolac) and combined inhibition of NO, PGs, KIR channels and Na+/K+‐ATPase (L‐NMMA+ketorolac+BaCl2+ouabain). In control, exercise blunted PE‐mediated vasoconstriction (%ΔFVC) compared to ADO (‐21±3% vs ‐46±6%; P<0.05) and this was unchanged with L‐NMMA+ketorolac (‐24±3% vs ‐47±5%). The addition of BaCl2+ouabain had no effect on vasoconstriction during exercise (‐27±3%), indicating that activation of KIR channels and Na+/K+‐ATPase is not obligatory to blunt sympathetic vasoconstriction in contracting human muscle.

Support HL102720
Sex differences in forearm vasoconstrictor response to voluntary apnea (1171.1)
Authors: Muller Matthew , Patel Hardikkumar , Heffernan Matthew , Ross Amanda
Published: June 2021

Clinical evidence indicates that obstructive sleep apnea is more common and more severe in men compared to women. Sex differences in the vasoconstrictor response to hypoxemia‐induced sympathetic activation might contribute to this clinical observation. In the current laboratory study, we determined sex differences in the acute physiological responses to maximal voluntary end‐expiratory apnea (MVEEA) during wakefulness in healthy young subjects (ten women, nine men, 26 ± 1 yrs). In addition, we studied eight postmenopausal women (62 ± 2 yrs) to determine the effect of menopause status. Mean arterial pressure (MAP), heart rate (HR), brachial artery blood flow velocity (BBFV, Doppler ultrasound) and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were measured and changes in physiological parameters from baseline were compared between groups. The breath hold duration and oxygen saturation nadir were similar between groups. In response to MVEEA, young women had significantly less forearm vasoconstriction compared to young men (ΔBBFV: 2 ± 7 versus ‐25 ± 6% and ΔCVC: ‐5 ± 4 versus ‐31 ± 4 %) whereas ΔMAP (12 ± 2 versus 16 ± 3 mmHg) and ΔHR (4 ± 2 versus 6 ± 3 bpm) were comparable between groups. The attenuated forearm vasoconstriction in young women was not observed in postmenopausal women (ΔBBFV ‐21 ± 5%). We conclude that young women have blunted forearm vasoconstriction in response to MVEEA compared to young men and this effect is not evident in older postmenopausal women. These data suggest that female sex hormones dampen neurogenic vasoconstriction in response to apnea‐induced hypoxemia.

Grant Funding Source: Supported by NIH P01 HL096570 and UL1 TR000127
Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in aerobic and resistance athletes (1172.1)
Authors: Smith Michael , Hamlin Robert , Devor Steven
Published: June 2021

Recent reports have indicated that resistance exercise training performed absent an aerobic exercise program may increase arterial stiffness. Our purpose was to compare the augmentation index (AIx) and left ventricular wasted pressure energy (LVEW) as markers of arterial stiffness and ventricular‐vascular coupling efficiency in young aerobic (AT) and resistance (RT) trained athletes. We also investigated the relationship between muscle sympathetic nerve activity (MSNA) and AIx to determine if sympathetic outflow could explain any observed differences in arterial stiffness.

Methods: MSNA (via microneurography of the peroneal nerve) was measured in 15 male subjects (8 RT, 7 AT). Aortic pressure waveforms were synthesized using applanation tonometry of the radial artery to derive AIx and LVEW values.

Results: RT subjects had greater AIx (12 ± 3 vs. ‐7 ± 2; P<0.01), LVEW (429 ± 111 vs. ‐360 ± 77; P<0.01) and MSNA burst incidence (109 ± 23 vs. 31 ± 5; P<0.01) than AT subjects. MSNA burst incidence was also significantly related to AIx in all subjects (R2=0.61; P<0.01).

Conclusions: A positive association was found between MSNA and AIx in young males. Furthermore, a history of RT is associated with increased arterial stiffness and elevated sympathetic outflow.
Muscle metaboreflex activation during dynamic exercise evokes epinephrine release resulting in β2‐mediated vasodilation (1172.2)
Authors: Kaur Jasdeep , Spranger Marty , Hammond Robert , Krishnan Abhinav , Alvarez Alberto , Augustyniak Robert , O’Leary Donal
Published: June 2021

Muscle metaboreflex‐induced increases in mean arterial pressure (MAP) during submaximal dynamic exercise are mediated principally by increases in cardiac output. To what extent, if any, the peripheral vasculature contributes to this rise in MAP is debatable. In several studies we observed that in response to muscle metaboreflex activation (MMA; induced by partial hindlimb ischemia), small but significant vasodilation occurred within the non‐ischemic vasculature (termed non‐ischemic vascular conductance; NIVC). We hypothesized that these increases in NIVC may stem from a metaboreflex‐induced release of epinephrine (Epi) resulting in β2‐mediated dilation. We measured NIVC and arterial plasma Epi levels in chronically instrumented dogs during rest, mild exercise (3.2 kph) and MMA before and after β‐blockade (propanolol; 2 mg/kg), α‐blockade (prazosin; 50 µg/kg) and α+β‐blockade. Both Epi and NIVC increased significantly from exercise to MMA: 81.9 ± 18.6 to 141.3 ± 22.8 pg/ml and 33.8 ± 1.5 to 37.6 ± 1.6 ml/min/mmHg, respectively. These metaboreflex‐induced increases in NIVC were abolished after β‐blockade (27.6 ± 1.8 to 27.5 ± 1.7 ml/min/mmHg) and potentiated after α‐blockade (36.6 ±2.0 to 49.7 ±2.9 ml/min/mmHg) while α+β‐blockade also abolished any vasodilation (33.7 ± 2.9 to 30.4 ± 1.9ml/min/mmHg). We conclude that MMA at mild exercise induces epinephrine release causing β2‐mediated vasodilation.

Grant Funding Source: HL‐55743
Modulation of N‐type Ca2+ currents by agmatine via imidazoline I2 receptor activation in rat coeliac ganglion neurons (1172.4)
Authors: Chung Seungsoo
Published: June 2021

Agmatine, an imidazoline deriviatives, suppress the vasopressor sympathetic outflow to produce hypotension. This effect has been known to be mediated in part by suppressing sympathetic outflow via acting imidazoline I2 receptors (IR2) at postganglionic sympathetic neurons. But, the cellular mechanism of IR1‐induced inhibition of noradrenaline (NA) release is still unknown. We therefore, investigated the effect of IR1 activation on voltage‐dependent Ca2+ channels which is known to play an pivotal role in regulating NA in rat coeliac ganglion neurons, using the conventional whole‐cell patch‐clamp method. In the presence of rauwolscine (3 uM), which blocks a2‐adrenoceptor (Ra2), agmatine inhibited voltage‐dependent Ca2+ current (ICa) by about 30%. This agmatine‐induced inhibition was almost completely prevented by efaroxan (10 uM) which blocks IR1 as well as Ra2. In addition, w‐conotoxin (CgTx) GVIA (1 uM) occluded agmatine‐induced inhibition of ICa, but, agmatine‐induced ICa inhibition was not affected by pertussis toxin (PTX) nor shows any characteristics of voltage‐dependent inhibition These data suggest that agmatine inhibit voltage‐dependent N‐type Ca2+ current (ICa–N) via activating IR1. Finally, agmatine significantly decreased the frequency of AP firing in a partially reversible manner. This inhibition of AP firing was almost completely occluded in the presence of w‐CgTx. Taken together, our results suggest that activation of IR2 in coeliac ganglion neurons reduced ICa–N in a PTX‐and voltage‐insensitive pathway, and this inhibition attenuated repetitive AP firing in coeliac ganglion neurons.
Influence of fitness on the pressor response following spontaneous bursts of muscle sympathetic nerve activity (1172.6)
Authors: Restaino Robert , Credeur Daniel , Holwerda Seth , Fadel Paul
Published: June 2021

Previous studies suggest that high fit (HF) subjects may exhibit altered vascular responses to reflex mediated increases in muscle sympathetic nerve activity (MSNA). Whether the ability of MSNA to modulate arterial blood pressure (BP) on a beat‐to‐beat basis is affected by fitness is unknown. In 7 HF (VO2 max=67±2 ml/kg/min) and 7 average fit (AF; VO2=44±2 ml/kg/min) young men, MSNA (microneurography) and blood pressure (Finapres) were continuously measured at rest for 10 minutes. Signal averaging was used to characterize beat‐by‐beat changes in mean arterial pressure (MAP) for 10 cardiac cycles following each individual MSNA burst and a peak response calculated. Variations in MSNA burst pattern were considered by comparing single (bordered by >1 heartbeat lacking MSNA) vs. multiple bursts. Changes in MAP were also calculated following heartbeats without MSNA (i.e., non‐bursts). In response to single MSNA bursts, no significant difference was noted in MAP (HF: +2.8±1.2 vs. AF: +1.8±0.34 mmHg, P>0.05); however, multiple bursts produced a significantly greater increase in MAP in HF subjects (HF: +4.8±0.5 vs. AF: +3.4±0.3 mmHg, P<0.05). Also, following non‐bursts, HF subjects tended to have a greater reduction in MAP (HF: ‐1.3±0.3 vs. AF: ‐0.7±0.1, P=0.053). These preliminary findings suggest a greater role for spontaneous MSNA bursts in modulating BP on a beat‐to‐beat basis in HF compared to AF subjects.

Grant Funding Source: Supported by NIH Grant RO1 HL093167 (PJF)