bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNS Gαi2 proteins participate in the central neural regulation of sodium and water homeostasis and in countering salt‐sensitive hypertension
Authors: Wainford Richard David , Kapusta Daniel R 
Published: June 2021

HypothesisCentral Gαi2‐protein gated pathways mediate the renal sympathoinhibitory, natriuretic and diuretic responses to acute volume expansion (VE) and counter the development of salt‐sensitive hypertension.MethodsSprague‐Dawley rats were pre‐treated (24h) intracerebroventricularly (i.c.v.) with a scrambled (S) or Gαi2 oligodeoxynucleotide (ODN; 25 μg). Changes in renal sympathetic nerve activity (RSNA), natriuresis and diuresis evoked by acute i.v. isotonic saline VE (5% body weight) were examined. In chronic studies rats were fed normal 0.4% (NS) or high 8% (HS) NaCl chow for 21‐days and brain Gαi2 protein levels were determined (N=6/gp). Separate rats were maintained on NS or HS and infused i.c.v. with a Gαi2 or S ODN, after 21‐days MAP and renal function were assessed (N=4/gp).ResultsCentral Gαi2‐protein down‐regulation attenuated the renal sympathoinhibitory (peak ΔRSNA [% control] S 43±3 vs. Gαi2 88±8, P<0.05 N=4), natriuretic (peak ΔUNaV [μeq/min] S 40±3 vs. Gαi2 26±3, P<0.05 N=6) and diuretic (peak ΔUV [μl/min] S 309±12 vs. Gαi2 225±26, P<0.05 N=6) responses to i.v. VE. In chronic studies HS intake selectively increased Gαi2 protein levels (5.8 fold, P<0.05) in the PVN. When infused with i.c.v. Gαi2 ODN, rats maintained on HS (but not NS) retained sodium (24h Na balance [meq/day] NS + Gαi2 0.3±.0.1 vs. HS + Gαi2 2.75±0.4, P<0.05), retained water (24h H2O balance [ml/day]; NS + Gαi2 12.6±1.3 vs. HS + Gαi2 29.4±3.6, P<0.05) and developed hypertension (MAP [mmHg]; NS + Gαi2 129±2 vs. HS + Gαi2 147±3, P<0.05).ConclusionThese data demonstrate that central Gαi2‐protein gated pathways contribute to the renal sympathoinhibitory and natriuretic responses to acute VE and participate in maintaining sodium and water homeostasis and normotension during high salt challenge. AHA 2250585, DK43337, HL071212, AHA 0855293E, P20 RR018766
Potential Role of NADPH Redox in Regulating Thiol Oxidation‐Elicited Subunit Dimerization Activation of Protein Kinase G in the Relaxation of Bovine Pulmonary Arteries to Pentose Phosphate Pathway Inhibitors
Authors: Neo Boon Hwa , Wolin Michael 
Published: June 2021

We have previously provided evidence that inhibition of glucose‐6‐phosphate dehydrogenase (G6PD) in the pentose phosphate pathway promotes oxidation of NADPH, and elicits vascular relaxation through coordinating multiple processes that lower intracellular calcium. Since it was reported that H2O2 induces coronary relaxation associated with a NO/cGMP‐independent thiol oxidation/subunit dimerization activation of protein kinase G (PKG), we investigated if inhibition of G6PD activates PKG through disulfide‐mediated subunit dimerization under conditions where relaxation of isolated endothelium‐removed bovine pulmonary arteries (BPA) is observed. BPA precontracted with 20mM KCl under hypoxic conditions were exposed to either 1mM 6‐aminonicotinamide (6‐AN) or 0.5mM epiandrosterone (Epi) to inhibit G6PD. It was observed that both 6‐AN and Epi increased PKG dimerization under conditions where relaxation was observed. These responses were associated with increased phosphorylation of vasodilator‐stimulated phosphoprotein (VASP) at the serine‐239 site known to be mediated by PKG. Thus, inhibition of G6PD promotes thiol oxidation‐elicited dimerization activation of PKG, suggesting that PKG activation is likely to be a participant in mechanisms through which cytosolic NADPH oxidation promotes vascular relaxation.Supported by NIH grants HL31069, HL43023 and HL66331
Early recovery from large‐strain lengthening contractions is not compromised in dysferlin‐null skeletal muscle
Authors: Roche Joseph A , Ru Lisa W , Bloch Robert J 
Published: June 2021

The recovery of dysferlin‐null skeletal muscles from injurious large‐strain lengthening contractions is delayed due to extensive necrosis and inflammation that peaks 3 days after injury. Here we test the hypothesis that muscles of dysferlin‐null A/J mice and control A/WySnJ mice recover during the first few hours after large‐strain injury, but that A/J muscle subsequently undergoes secondary damage leading to a loss of contractile torque.METHODSWe studied the response to injury from 15 large‐strain lengthening contractions in the tibialis anterior muscle of A/J and A/WySnJ mice. We measured contractile torque and assessed morphological changes in muscle ~ 10 min and 3, 6, 12, 24, 48 and 72 hrs after injury.RESULTSChanges in torque and counts of necrotic fibers after injury are shown in Table 1 (*, p<0.05 A/W Vs A/J; †, p<0.05 compared to 3 hrs).
Contractile torque and counts of necrotic fibers after injury

Mouse
Uninjured
~ 10 min
3 hrs
6 hrs
12 hrs
24 hrs
48 hrs
72 hrs

Torque (% Pre‐injury) Mean ± S.D.
A/WySnJ
100
62 ± 2
87 ± 2
92 ± 5
85 ± 10
89 ± 5
85 ± 5
95 ± 6

A/J
100
66 ± 4
78 ± 7
75 ± 0*
70 ± 5*
70 ± 5*
62 ± 1*†
64 ± 9*†

Necrotic fibers(% total # fibers counted) Mean ± S.D.
A/WySnJ
0.2 ± 0.5
1 ± 2
2 ± 1
2 ± 1
2 ± 3
3 ± 2
3 ± 4
2 ± 2

A/J
1 ± 1
2 ± 2
7 ± 4*
9 ± 6*
8 ± 4*
18 ± 14*†
19 ± 9*†
23 ± 8*†

CONCLUSIONSDysferlin‐null muscle recovers as well as control by 3 hrs following injury, after which it gradually loses contractile torque and necrotic fibers appear.This work was funded by the Jain Foundation Inc.
Exercise limitation, muscle atrophy and increased angiopoietin mRNA in a mouse model of pulmonary TNFa induced inflammation
Authors: Tang Kechun , Wagner Peter D , Breen Ellen C 
Published: June 2021

Many chronic inflammatory diseases exhibit high circulating TNFa and skeletal muscle weakness. In this study, a mouse model of chronic pulmonary inflammation due to SP‐C driven TNFa overexpression was used to evaluate the effects of systemic TNFa on exercise capacity and locomotor skeletal muscle expression of atrophy and angiogenic genes. SP‐C/TNFa (+/−) mice (female, 6–8 months of age) had a 5.7‐fold increase in serum TNFa levels compared to littermate controls (29.6±9.6 vs. 5.2±3.5 pg/ml, p<0.001), reduced body weight (25.9±3.3 vs. 32.0±4.6 g, p=0.028, n=4), soleus mass (7.7±1.2 vs. 9.6±2.2 mg, p=0.021) and treadmill running endurance (60±9 vs. 81±11 min, p=0.016). In the soleus, PGC‐1a mRNA levels, measured by real time RT‐PCR, were decreased in the TNF(+/−) mice compared to control (1.6±0.4 vs. 3.1±1.4 units, p=0.014), and angiopoieitn‐1 mRNA was increased (51.5±15.9 vs. 10.0±6.3 units, p<0.001). These data suggest (1) prolonged high systemic TNFa levels alter skeletal muscle metabolism and function; (2) PGC‐1a, an important metabolic regulator, may be a key factor in inflammation associated muscle atrophy; (3) TNFa regulation of muscle angiopoietin‐1 has a potential role in protecting vascular integrity in chronic systemic inflammatory conditions.NIH/NHLBI 1 P01 HL091830‐01A1
Regulatory volume increase in single mouse soleus muscle fibres assessed simultaneously using intracellular fluorescence and fibre width
Authors: Lindinger Michael I , Leung Matt , Moynes Jaclyn , Shortreed Karin E , Hawke Thomas J 
Published: June 2021

Mammalian skeletal muscle cells have the ability to regulate volume in response to increases or decreases in extracellular osmolarity. In the present study we measured the time course of change in single fibre intracellular calcein fluorescence (volume indicastor) and width in response to varied 200 mosmol/L increase in extracellular osmolarity using NaCl or sucrose. Adult mouse EDL single fibres were isolated using collagenase and incubated in DMEM prior to and during experimentation. Fibres were loaded with calcein‐AM for 30 min, and triple‐rinsed with calcein‐free DMEM. After obtaining baseline images NaCl or sucrose solution was added. Fibre images were obtained at 3–6 s intervals for up to 60 min. Fibre images were analyzed for intensity and width at 2–3 sites. Increased osmolarity resulted in a rapid increase in fibre fluorescence and decrease in fibre width. Both variables gradually recovered to baseline values within ~45 min. Bumetanide, an inhibitor of the sodium‐potassium‐2 chloride cotransporter (NKCC) impaired recovery. There was a linear relationship between increases in fibre fluorescent intensity and decreases in fibre width. It is concluded that the NKCC is involved in regulatory volume increase in skeletal muscle, and that changes in fluorescence intensity can be used as an indicator of changes in cell volume.Supported by NSERC of Canada.
Doxorubicin stimulates catabolism in C2C12 myotubes
Authors: Gilliam Laura A. A. , Moylan Jennifer S. , Patterson Elaine W. , Wilson Anne S. , Reid Michael B. 
Published: June 2021

Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing chemotherapy. Previous studies in mice show that the E3 ubiquitin ligase, MAFbx/atrogin‐1 is upregulated in skeletal muscle following doxorubicin administration, an effect regulated by p38 MAPK signaling. Activation of p38 MAPK also promotes caspase‐3 activation. These findings led us to hypothesize that doxorubicin causes skeletal muscle atrophy through p38 MAPK signaling, leading to the upregulation of MAFbx/atrogin‐1 and caspase‐3. We measured the loss of myofibrillar proteins in C2C12 myotubes exposed to doxorubicin (0.2 μM, 48 hrs). Compared to control, actin (mean ± SE; −49 ± 4 %, n=3, p<0.01) and myosin (−40 ± 9 %, n=11, p<0.05) proteins decreased. p38 MAPK phosphorylation was elevated in 30 mins following doxorubicin exposure (16 ± 3 %, n=6, p<0.05). Doxorubicin increased MAFbx/atrogin‐1 mRNA 16 hrs (74 ± 8%, n=3, p<0.01) and 24 hrs (132 ± 8 %, n=3, p<0.01) following exposure. Caspase‐3, both precursor and active form, were elevated 6 hrs (precursor: 25 ± 7 %, n=3, p<0.05; active: 125 ± 35 %, n=3) and 24 hrs (precursor: 36 ± 6, n=3, p<0.01; active: 87 ± 12 %, n=3, p<0.01) following doxorubicin. Our data shows that doxorubicin causes skeletal muscle protein loss, which may be mediated through p38 MAPK signaling and upregulation of MAFbx/atrogin‐1 and caspase‐3.Supported by: T32 HL086341‐02 (EWP) and AHA predoctoral fellowship(LAAG)
The time course appearances of isometric contractile properties and muscle‐specific proteins in a novel three‐dimensional skeletal muscle model
Authors: Nakamura Tomohiro , Yamasaki Kenichi , Fujisato Toshia 
Published: June 2021

C2C12 cells were embedded in type‐I collagen gel solution at density of 1.0 × 107 cells/ml. The suspension was added to two artificial tendons(elastase treated porcine aorta). The medium was cultured for 2 days in growth medium and shifted to differentiation medium supplemented with 7% horse serum. The contraction force (F), the change ratio of contraction (dF/dt) and the change ratio of relaxation (dF/drt) were assessed at 7,14,21 days after onset of cultivation. The protein accumulation in myosin heavy chain (MHC) and electron micrograph (EM) were also assessed at 7,14,21 days after cultivation.Up to 14 days, F, dF/dt and dF/drt increased dramatically. In addition, the protein accumulations of α‐actin, fast and slow MHC also increased markedly. From 14 days to 21 days, F, dF/dt, dF/drt increased gradually, however, the protein accumulations of α‐actin, fast and slow MHC did not show remarkable change. At 21 days, the sarcomere structures and basal lamina were evident by EM.These results suggest that the appearances of contractile properties do not quite correspond to the appearances of muscle‐specific protein at latter stage in maturation of three‐dimensional skeletal muscle cells.
Circadian rhythm of spontaneous activity and body temperature and its relationship with exercise capacity
Authors: Machado Frederico Sander Mansur , Rodovalho Gisele Veira , Coimbra Cândido Celso 
Published: June 2021

The aim of this study was to verify relationships between circadian spontaneous activity and body temperature (Tb) with exercise capacity in two different phases of light/dark cycle.Circadian activity and Tb of Wistar rats (n=11), under regular environmental conditions with free access to water and food, were continuously recorded using a telemetric sensor (G2 E‐Mitter) chronically implanted (ip) 3 days before. We accessed total time to fatigue, workload and Tb during exercise. Animals were submitted to progressive exercise test protocols until fatigue during the early light and dark phases. Each test was separated for 3 days. Fatigue was set as the moment when rats couldn't keep pace with treadmill.Results suggest increased circadian dark phase activity compared to light phase (p<0.01). This was accompanied by greater light phase exercise capacity and Tb variance and heat accumulation (p<0.05). There was no direct relationship of circadian activity and exercise capacity although at light phase a specific negative relationship of circadian temperature and exercise capacity was observed (r=−0.74, p<0.01).We demonstrated that circadian activity was not directly related to exercise capacity, despite the difference regarding exercise capacity and thermoregulation at two different circadian periods of rat activity.Supported by: CNPq and FAPEMIG
Post‐exercise hypotension: The effect of water drinking during exercise
Authors: Fukuba Yoshiyuki , Kajimoto Chie , Yamada Masako , Koga Shunsaku , Endo Masako Y 
Published: June 2021

There is commonly a sustained reduction in mean arterial blood pressure (MAP) after a prolonged exercise, even in normotensive individuals, i.e., post‐exercise hypotension (PEH). Since the lowered pre‐load is supposed to be one of the potential causes of PEH, due to the decreased plasma volume (PV) via dehydration during exercise, we aimed to explore the effect of water drinking to PEH. Nine male subjects undertook 60‐min leg cycle ergometer exercise at work rate of 60 % of heart rate (HR) reserve without (C protocol) or with (W protocol) oral water intake, followed by 30‐min of supine rest. Subjects remained at supine rest for a further 60‐min. In the W protocol, the subjects were able to drink the water with an ad‐lib manner (~600 ml) during exercise to adjust the exercise‐induced reduction of body weight. The HR, MAP, and relative change (Δ) of PV were measured throughout the protocol. The MAP in C protocol was substantially reduced during recovery (~5 mmHg; p<0.05), compared to pre‐exercise level. In contrast, MAP in W protocol did not show the substantial reduction during recovery, and was significantly higher to those in C protocol. The ΔPV was not different during recovery between both protocols. These results indicate that PEH seems unlikely to be association to the factor related to the PV change, while oral water intake per se has an unsolved influence to post‐exercise MAP.(Support: JSPS‐KAKENHI, 20700526, 21370111)
Intra‐individual Reproducibility of Hyperemic Responses to Ischemic Exercise
Authors: Lopez Marcos G. , Casey Darren P. , Silva Bruno M. , Walker Branton G. , Joyner Michael J. 
Published: June 2021

We examined the reproducibility of the hyperemic response to ischemic exercise (IE) in the forearm and compared the magnitude of this response to ischemia alone (reactive hyperemia, RH). Eight subjects (6M/2F; 26 ±1 yrs) performed 3 trials of IE and 2 of RH. IE consisted of 5 min of forearm ischemia with rhythmic forearm exercise (20% of max) during the final 2 min. RH consisted of 5 min of forearm ischemia. Peak and total (area under the curve) forearm blood flow (FBF; venous occlusion plethysmography) and blood pressure (MAP; Finometer) were measured for 3 min after each stimulus. Forearm vascular conductance (FVC; ml/100ml/min/mmHg) was calculated from FBF (ml/100ml/min) and MAP (mmHg). The mean intra‐individual coefficient of variation (CV) across the 3 IE trials was 13.0±1.4% and 16.3±1.2% for baseline‐adjusted peak FBF and FVC, respectively. The CVs for total FBF and FVC were 10.4±1.0% and 14.9±1.0%, respectively. Mean peak FBF was greater for IE compared to RH (37.3±2.7 and 30.0±1.3, P < 0.002), however mean peak FVC was not different (35.1±2.6 and 34.5±1.1, P = 0.80). Mean total FBF (67.6±3.9 and 18.0±2.5, P < 0.001) and mean total FVC (64.7±2.7 and 20.8±3.2, P < 0.001) were greater for IE compared to RH, respectively. Thus, our data suggest that the hyperemic response to IE is reproducible, and that the magnitude of this response is greater than that of ischemia alone.NIH HL‐46493 (MJJ), CTSA RR‐024150 and RR‐024152
Effect of mouse strain on mitochondrial biogenesis and exercise
Authors: Davis Greggory Ryan , Wang Pingyun , Hwang Paul M 
Published: June 2021

Sponsor: Jacqueline M. StephensPurposeImprovement in exercise capacity and change in mitochondrial DNA (mtDNA) were examined in B6 mice compared to wild‐type p53 and heterozygous FVB mice.MethodsFVB and B6 mice performed a high‐intensity five‐week treadmill exercise protocol. Maximal exercise testing was performed on all groups and time was recorded at the point of exhaustion. All groups were rested for 72 hours prior to dissection to minimize any acute effects of exercise. Body fat percentage was determined and the gastrocnemius and soleus muscles were harvested and analyzed.ResultsThe FVB strain nearly doubled work capacity and had a significantly lower body fat percentage compared to the B6 strain. mtDNA copy number did not change significantly in either strain and it actually decreased in the trained FVB p53 +/+ and p53 +/− groups.ConclusionsFVB mice demonstrated both a greater intrinsic exercise capacity as well as a greater response to exercise training while variation in the genotype of the FVB mice did not significantly affect response to exercise. The greater exercise capacity seen in the FVB mice may be due to a number of other factors including cardiovascular, biomechanical, and psychological aspects. It is also possible that exercise capacity may have increased due to genes mediated by nuclear DNA, making change in mtDNA more difficult to detect.National Heart, Lung, and Blood Institute. National Institutes of Health, Bethesda, MD 20892
Selective attenuation of carotid‐cardiac responses to hypertension at the onset of static handgrip in humans
Authors: Deo Shekhar H , Young Colin N. , Fairfax Seth T. , Fadel Paul J. 
Published: June 2021

Previous studies have indicated that at the onset of exercise cardiac baroreflex function is reduced in an intensity‐dependent manner, which appears to be mediated by a blunted ability to buffer hypertensive challenges. However, whether cardiac baroreflex responses to a hypotensive stimulus are altered at exercise onset is unclear. To examine this, ten subjects (25±1 years) performed multiple 1‐min bouts of static handgrip (HG) at 15 and 60% of maximal voluntary contraction (MVC), while breathing to a metronome set at eupneic frequency. Neck pressure (NP +40 Torr) or neck suction (NS −60 Torr) was applied for 5s at end expiration, to simulate carotid baroreflex (CBR) hypotension and hypertension, respectively at rest, at the onset of HG (<1 s), and at ~40 s of HG. Cardiac responses to NP at the onset of exercise were maintained at both HG intensities, whereas heart rate responses to NS were blunted at exercise onset during 60% MVC HG (−16±2 rest vs. −9±3 bpm 60% MVC; P<0.05) but preserved at 15% MVC. The response range of the carotid‐cardiac baroreflex at the onset of 60% MVC HG was reduced (25±1 rest vs. 18±3 bpm 60% MVC; P<0.05) compared to rest and 15% MVC. Heart rate responses to NP and NS applied at ~40s of 15 and 60% MVC HG were similar to rest. These results suggest that carotid‐cardiac responses to hypertension are selectively contributing to an impaired CBR control of heart rate at the onset of static HG in humans.Support: NIH R01HL093167
Diet‐Induced Obesity Causes Selective Insulin Resistance
Authors: Bardgett Megan , Stocker Sean D 
Published: June 2021

Peripheral insulin resistance is a hallmark characteristic of the metabolic syndrome and obesity. However, whether obesity causes insulin resistance in brain is not known. To test this hypothesis, male Sprague‐Dawley rats (200–250g) were fed a moderately high‐fat diet (32% kcal as fat) or a low fat (LF) diet (10.6% kcal as fat). After 13 weeks, the body weights of rats fed the moderately high‐fat diet segregated into obesity‐prone (OP, 793±13 g) and obesity‐resistant (OR, 596±8 g) groups. The control group consisted of young adult rats (292±22 g, n=4) or rats fed LF (612±15 g, n=4). Rats were anesthetized with α‐chloralose and infused with insulin (3.75 mU/kg/min) and 50% dextrose (.25–.75 ml/hr) for 120 min. Baseline plasma insulin levels were significantly elevated in OP compared to OR and control rats (OP: 16±2 vs OR: 8±1 and control: 11±1 ng/ml, p<0.05). As expected, glucose utilization was significantly reduced in OP rats (OP: 3.3±0.7 vs OR: 5.5±0.9 and control: 7.5±0.8 mg/kg/min, p<0.05). Interestingly, hyperinsulinemia produced similar increases in lumbar sympathetic nerve activity across groups (OP: 127±6%; OR: 128±9%, control: 133±10% P>0.05). Arterial blood pressure decreased significantly by 120 min in all groups (OP: 94±4 vs 84±3 mmHg; OR: 94±7 vs 87±6 mmHg, control: 100±7 vs 85±6, P<0.05). These findings indicate that obesity causes peripheral but not central insulin resistance.Supported by NIH HL090826, AHA 0630202N & 0815372D
Environmental Enrichment Does Not Impact the Emergence of Repetitive Behavior in the C58/J Inbred Strain, A Novel Mouse Model of Autistic‐Like Behavior
Authors: Hess Christina , Johnson Ashley , Wahby Hady , Yano Hiroshi , Ryan Bryce 
Published: June 2021

Autism has three core symptoms: restricted, repetitive behaviors, deficits in communication, and abnormal social interactions. The causes of autism are unknown, and no established animal model currently exists. Past research indicates that the inbred C58/J mouse strain has elevated repetitive behaviors and deficits in social behavior, making this an animal of interest in the research of autism and its underlying causes. This study expands on the earlier work and investigates the effects of environmental enrichment during development on the emergence of abnormal behaviors in the C58/J mouse. Breeding pairs of mice were placed in enriched or non‐enriched caging and the behavior of their pups was measured throughout the lactational period. Home cage activity levels of adult mice reared in different environments were also measured. C58/J pups showed elevated activity at a young age when compared to control mice and demonstrated emergence of repetitive behaviors in the second week of life. Adult C58/J mice showed no difference in home cage activity compared to control mice, but do retain elevated repetitive behaviors throughout life regardless of the level of enrichment in which they were raised.This research was supported by NIMH 1R21MH084132‐01A1 and the University of Redlands Science Center.