bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of acute and chronic intermittent hypoxia on apnea severity
Authors: Yokhana Sanar S , Gerst David G , Badr M. Safwan , Lee Dorothy S , Carney Laura M , Mateika Jason H.
Published: June 2021

This study was designed to determine the impact of intermittent hypoxia (IH) on apnea severity. Thirteen participants with sleep apnea (OSA) completed the study. A baseline sleep study (SS) was completed on day 1. On day 2, participants were exposed to 12 episodes of hypoxia immediately before completing a SS. Thereafter, participants were exposed to IH on nine consecutive days. On day 11, participants were exposed to IH before completing a SS. Five OSA participants completed an identical protocol while exposed to episodes of room air. The hypoxic ventilatory response (HVR − Δ VE/Δ SaO2) and long‐term facilitation of VE (vLTF) were measured each day. The apnea/hypopnea index (AHI) after exposure to IH on day 2 was greater than baseline in the IH but not the placebo group (IH group − 42.0 ± 5.9 vs. 26.6 ± 3.8 events/hr, p = 0.02; Placebo − 37.6 ± 11.3 vs. 30.3 ± 8.0 events/hr, p = 0.3). The AHI on day 11 (39.0 ± 6.2, p < 0.04) was also greater than baseline; however the AHI was similar to that measured on day 2. The HVR measured prior to exposure to IH on day 2 was correlated to the baseline AHI (r = 0.8, p < 0.002). Likewise, on day 2, the AHI was correlated to the HVR measured during the last hypoxic episode and vLTF (r = 0.58, p < 0.04 for both HVR and vLTF). In conclusion, exposure to IH is associated with an increase in the AHI. Increases in the HVR or vLTF might in part be responsible for increases in the AHI.

Funding: NIH (HL‐085537)
Morphine suppresses augmented breaths independently of changes in hypoxic chemosensitivity or central respiratory drive
Authors: Bell Harold James , Kehoe Valerie , Haouzi Philippe A
Published: June 2021

The link between opioid therapy and central sleep disordered breathing (SDB) is not known. Since augmented breaths (ABs) are known to destabilize breathing, we sought to determine whether opioid therapy increases the prevalence of ABs, and thereby exacerbates SBD. We therefore monitored unanesthetized, unrestrained male rats in room air RA and hypoxia (10% O2), before and after a single dose of morphine (5 mg/kg s.c.). Morphine suppressed ABs from 2.0 ± 0.0 in a 5 min observation window, to nil (0.0 ± 0.0). The normal hypoxia‐induced facilitation of ABs was suppressed by morphine (14.8 ± 4.8 vs. 6.0 ± 2.6 ABs in 5 min). VE was increased slightly after morphine in RA (82 ± 6 vs. 115 ± 21 ml/min/100g). During hypoxia VE was unchanged by morphine administration (160 ± 16 vs. 160 ± 17 ml/min/100g), indicating that hypoxic chemosensitivity was unaffected at this dose. Breathing frequency was significantly depressed by morphine but only during exposure to hypoxia (170 ± 23 vs. 127 ± 10 bpm). Nevertheless, the suppression of ABs by morphine was 2.5 fold greater than the observed decrease in breathing frequency. Our results suggest that morphine does not exacerbate central SDB via an increased prevalence of ABs. Rather, morphine suppresses ABs, even at a dose that does not depress either hypoxic chemosensitivity or central respiratory drive.
Ethics and Scientific Publication, Case Studies in Discussion Format
Authors: Fallon John F.
Published: June 2021

We will engage each other in discussion about the roles and responsibilities authors, editors, reviewers and readers play in ethical considerations involved with academic publication. Ethical conflicts may arise in each of these levels of the publication process. We will discuss how this may occur and how it is identified and handled. To do this I will present two or three publication case histories to focus the discussion. Participants should be prepared to explore the ethics of academic publication, so that all participants will walk away with a synthesis of how problems arise, who has the responsibility to raise questions and how to resolve the issues.
Regulation of Force Dynamics in Fast Twitch Muscle
Authors: Groenendaal Willemijn , Jeneson Jeroen , Wiseman Robert , Nicolay Klaas , Hilbers Peter , van Riel Natal
Published: June 2021

Several regulatory steps controlling skeletal muscle force generation have been experimentally demonstrated, and mathematical models have been developed to understand these mechanisms. Here, we investigated the minimal set of mechanisms required to describe both the range in peak force from twitch to tetanus and the characteristics of contraction and relaxation. Hereto, we measured calcium fluorescence using Rhod‐2 and force kinetics in murine EDL muscles at different stimulation frequencies, ranging from twitch to tetanus. Next, we tested available models in literature with a validated spatiotemporal calcium model as input. Monte Carlo simulations, covering a large parameter space, have been performed to test if the evaluated force models could describe the force dynamics.

These simulations showed that calcium activation of the cross bridges sufficed to describe the increment in force from twitch to tetanus. In addition, numerical analysis indicated that extending the models with cooperative activation through strongly attached cross‐bridges was required to reproduce the dynamics of contraction and especially of relaxation. Therefore, we hypothesize that the minimal set of mechanisms to describe force dynamics in fast twitch muscle includes both activation by calcium bound to troponin and cooperative activation through strongly attached cross‐bridges.
The inhibition of phosphodiesterase 4 reduces skeletal muscle protein catabolism by suppressing autophagy/lysosomal and proteasomal pathways and atrophy‐specific gene transcription
Authors: Lira Eduardo Carvalho , Parreiras‐e‐Silva Lucas Tabajara , Zanon Neusa Maria , da Costa Neto Cláudio Miguel , do Carmo Kettelhut Ísis , Navegantes Luiz Carlos Carvalho
Published: June 2021

This work investigated the effect of cAMP through PDE4 inhibition, the major PDE expressed in skeletal muscle, in modulating muscle protein degradation.

The protein catabolism was monitored indirectly by measurement of interstitial tyrosine concentration in tibialis anterior muscle from Wistar rats (~250g) by microdialysis. Muscles were perfused with selective PDE 4 inhibitor, rolipram (1mM). Rates of proteolysis were determined by measuring the tyrosine release from extensor digital longus (EDL) and soleus from rats (~70g) incubated with different concentrations of PDE inhibitor. Gene expression was measured by real time‐PCR and cAMP level was estimated by ELISA. In situ muscle perfusion with rolipram reduced interstitial‐arterial tyrosine concentration difference, indicating a reduction in protein catabolism. Rolipram in vitro reduced overall proteolysis in a dose‐dependent manner and increased the muscle level of cAMP. This effect was accompanied by a decrease in the ubiquitin‐proteasome system (UPS) activity and suppression of autophagic and Ub‐ligases (atrogin‐1 and MuRF‐1) gene expression induced by fasting.

These findings identify mechanisms by which PDE inhibitors reduces protein degradation, suggesting that inhibition of PDE 4 activates cAMP‐dependent pathway, which leads to the suppression of autophagic and UPS pathways and atrophy‐specific gene transcription.
Peak force controls intracellular signaling after high force contractions, independent of metabolic stress
Authors: Rahnert Jill A , Burkholder Thomas J
Published: June 2021

The increase in protein synthesis following resistance exercise has been attributed to the high forces generated, and activation of several signaling cascades appears to be force dependent. Both mechanical and metabolic stresses are present, and ATP depletion is aggravated by high duty cycle (HDC) protocols (i.e. 30% work:rest). We hypothesized that contraction‐induced signaling may reflect mechanical stress more than metabolic stress. Mechanical stress induced signaling was discriminated from metabolic stress by using low duty cycle (LDC, 2%) and HDC (30%) protocols. Mouse tibialis anterior muscles were subjected to 60 maximal isometric activations over 20 minutes and analyzed by Western blot. Peak forces were similar (1.31 N ± 0.25, HDC and 1.22N ± 0.22, LDC). Force decline was greater in the HDC (29%) than LDC (3%). Phosphorylation of ACC, indicative of AMP‐activated protein kinase (AMPK) activity, was markedly increased in the HDC protocol. Force generation of any duration reduced phosphorylation of Akt, increased ERK1/2, and had no effect on p70s6k or 4EBP1. Phosphorylation of p38 was greater in the LDC than HDC protocol. We conclude that the immediate response to high force contractions is largely dependent on mechanical stress with the exception that p38 phosphorylation is reduced by metabolic stress. Supported by DC05017
Mitochondrial function is not the same in rat diaphragm and limb muscles
Authors: Garcia‐Cazarin Mary L , Gamboa Jorge L , Andrade Francisco H
Published: June 2021

The mitochondrial content of skeletal muscles is proportional to their activity levels, supposedly to match ATP supply to demand. This view excludes the existence of intrinsic differences in mitochondrial function. The diaphragm is a constantly active respiratory muscle with high mitochondrial content. This study tested the hypothesis that mitochondrial function differs in rat diaphragm and triceps surae (TS, limb muscle). Mitochondria isolated from diaphragm and TS muscles of adult male Sprague Dawley rats were used to measure O2 consumption with polarography, the content of respiratory complexes, uncoupling protein 2 and 3 (UCP2 and UCP3) and voltage dependent anion channel 1 (VDAC1) by western blot, and complex IV activity by spectrophotometry. Respiration states 3 (substrate‐ and ADP‐driven) and 5 (uncoupled) were 27±8% and 24±10% lower in diaphragm than in TS mitochondria (p<0.05 for both). However, the contents of respiratory complexes III, IV and V and VDAC1 were higher in the diaphragm than in TS (23±6%, 30±8%, 25±8% and 18±8% respectively, p≤0.02 for all comparisons). Likewise, complex IV activity was 64±16% higher in diaphragm mitochondria (p=0.01). UCP2 and UCP3 content was not different. These data indicate that diaphragm mitochondria respire at lower rates, despite a higher content of respiratory complexes. The results support our initial hypothesis and suggest that in the diaphragm mitochondrial content is not the only determinant of aerobic capacity. We propose that VDAC1 influences ATP production in the diaphragm by regulating mitochondrial respiration.

Research supported by R01 EY012998‐08A1 to FHA.
Coordinated maintenance of the size control of muscle cells by AMP‐activated protein kinase
Authors: Lantier Louise , Mounier Rémi , Leclerc Jocelyne , Melki Judith , Pende Mario , Bertrand Luc , Foretz Marc , Viollet Benoit
Published: June 2021

Skeletal muscle mass is regulated by signaling pathways that govern protein synthesis and cell proliferation, the mammalian target of rapamycin (mTOR) playing a key role in these processes. Recent studies have suggested the crucial role of AMP‐activated protein kinase (AMPK) in the inhibition of protein synthesis and cell growth. Here, we address the role of AMPK in the regulation of muscle cell size in vitro and in vivo. The size of myotubes lacking both AMPKα1 and α2 catalytic subunits was 1.5‐fold higher than for controls. A marked increase in p70S6K Thr389 and rpS6 Ser235/236 phosphorylation was observed concomitant with an up‐regulation of protein synthesis rate. Inhibition of mTOR pathway by AMPK activators (AICAR, metformin, A‐769662) was blunted and was correlated with altered raptor phosphorylation. However, treatment with rapamycin prevented both p70S6K phosphorylation and cell hypertrophy. Moreover, in skeletal muscle‐specific deficient AMPKα1/α2 KO mice, soleus muscle showed a higher mass with myofibers of larger size and was correlated with enhanced p70S6K and rpS6 phosphorylation. Our results demonstrate the cross talk between AMPK and mTOR/p70S6K pathways in muscle cell size control.

ANR‐06‐PHYSIO‐026
Oxidative stress restores force loss in skeletal muscle following eccentric contractions
Authors: Hernández Andrés , Kosterina Natalia , Katz Abe , Westerblad Håkan
Published: June 2021

The role of oxidative stress in force recovery following eccentric contractions was examined in mouse EDL muscles. Isometric force was measured at 30, 70, and 150 Hz (0.5 ms pulse, 300 ms train) before, immediately after, and during a 60 min period following 10 eccentric contractions (stretched to 15% above optimal length during last 150 ms of 400 ms tetanus) at a train rate of 1 contraction every 4 s. Three groups were utilized: Control (C); H2O2, 100 μM was administered after the post‐eccentric contraction test; DTT, 5 mM was administered as in the H2O2 condition. The force immediately after eccentric contractions was decreased by ≈50% (30 Hz), ≈55% (70 Hz), and ≈45% (150 Hz) with no significant differences between groups (p>0.05). To compare recovery, force was normalized to each frequency's force immediately after eccentric contractions (i.e., post‐eccentric contraction force=100%). The effects of H2O2 and DTT on force recovery were most pronounced at 30 Hz. For instance, at 40 min normalized force was significantly higher (p<0.05) in H2O2 (125±7%) and lower in DTT (73±5%) in comparison to C (101±8%). In contrast, normalized force for H2O2 during 150 Hz stimulation was not significantly different from C or DTT at 40 min. These results indicate that oxidative stress is important for force recovery at low frequencies in skeletal muscle following eccentric contractions.
Functional muscle analysis of the Tcap knockout mouse
Authors: Markert Chad David , Childers Martin K.
Published: June 2021

Autosomal recessive limb‐girdle muscular dystrophy type 2G (LGMD2G) is an adult‐onset myopathy characterized by distal lower limb weakness, calf hypertrophy, and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z‐disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout mice carrying a null mutation in the TCAP gene. Here we present the first report of a Tcap knockout mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4‐month‐ and 12‐month‐old mice. Muscle histology of Tcap‐null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of TCAP was accompanied by increased protein levels of myostatin. Our Tcap‐null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild‐type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus muscles. Finally, a mechanical investigation of EDL and soleus indicated an increase in muscle stiffness in knockout animals. We are the first to establish a viable knockout mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.

Support: M.K. Childers Laboratory Startup Fund
Effect of combined inhibition of adenosine and nitric oxide on compensatory vasodilation during exercise with acute hypoperfusion
Authors: Casey Darren P. , Walker Branton G. , Roberts Shelly K. , Knutson Jean N. , Joyner Michael J.
Published: June 2021

Nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to hypoperfusion during exercise. We tested the potential for adenosine/NO interaction in the compensatory dilation. Eight males (25 ± 2 yrs) performed forearm exercise (20% of max) during intra‐arterial balloon inflation. Each trial included; exercise, exercise with balloon inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and brachial artery catheter pressure (BAP) were measured. Exercise was repeated during NO synthase inhibition (L‐NMMA) alone and with the combination of L‐NMMA/aminophylline (adenosine receptor blockade). Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from BF (ml/min) and BAP (mmHg). The % recovery in FVC during inflation was calculated as (steady state inflation plus exercise value – nadir)/[steady state exercise (control) value‐nadir]. FVC fell acutely with balloon inflation during all trials (P < 0.01). During the control trial, the % recovery in FVC was 111 ± 8%. The % recovery in FVC was attenuated with NOS inhibition alone (80 ± 9%; P < 0.001 vs. control) and attenuated further with combined inhibition of NO/adenosine (63 ± 9%; P < 0.05 vs. L‐NMMA). Thus, adenosine has an NO independent role in the compensatory vasodilatation during exercise with acute hypoperfusion.

NIH HL46493 (MJJ), AR55819 (DPC) and RR‐024150.
Effect of Jazz Dance on the Bone Marker, Metabolic Related Substrates and Energy Metabolic Regulation Hormones 20′ Female
Authors: Na Chan Il , Kim Donghee , Lee Hayan , Kwon Soyoung , Jung Jaekwan , Kim Heok , Yang Meehyun , Jung Woosuk , Moon Hyunwoong , Baek Changyei , Kim Daeyeol
Published: June 2021

The purpose of this study was to evaluate the effect of jazz dance on the bone metabolic related substrates and energy metabolic regulation hormones. The subjects for this study were 20 females and divided into 2 groups: jazz dance group(JD, n=10) and control group(CG, n=10). The jazz dance programs was warm up, cool down and main exercise 3 times a week for 12 weeks. And the change of bone metabolic related substrates(osteocalcine(OC), dexiripyridenoline(DPD)) and energy metabolic regulation hormones(growth hormone(GH), thyroxine(T4), insulin, glucagon, cortisol, epinephrine) had been measured. OC of the JD was increased after 12 weeks(p<.05). OC of the JD was higher after 12weeks of exercise(p<.05) than CG. DPD(p<.05) of the JD was decreased after 12 weeks(p<.05). And there was significant difference between the groups(p<.05). GH of the JD was increased after 12 weeks(p<.05) but there was no significant difference between the groups. Insulin and cortisol of the JD was decreased after 12 weeks(p<.05) and there was significant difference between the groups(p<.05). T4, glucagon, and epinephrine were no significant difference between the groups and time. It is concluded that aerobic activity, rapid music of jazz dance affect the positive bone metabolism and energy metabolic regulation with decreased life stress.
Improvement of exercise metabolism and carotenoids antioxidant scores with CordyMax and LifePak in young Chinese elite athletes
Authors: Duan Ligong , Zhao Liang , Liang Chen , Lu Jihong , Gao Ling , Li Guoping , Zhu Jia‐Shi
Published: June 2021

Cordyceps sinensis and its fermentation product, CordyMax (CM), are used for anti‐aging and health preservation. We have reported CM's anti‐fatigue and endurance enhancement functions in multi‐sport endurance Caucasians athletes (Chin J Clin Pharmacy 2007, 5:16). LifePak (LP) is enriched in carotenoids and antioxidant nutrients to improve antioxidant capability in young athletes (FASEB J 2009, 23:1007.3). We further tested the improvement of exercise metabolism and antioxidant capacity with CM and LP in a self‐controlled trial in young Chinese elite athletes (n=25, 18.1 yrs on average) recruited from China bicycle teams. They received CM 3.18 g/day and LP 2 sachets/day for 6 wks. All subjects remained on the same diet plan and training intensity during the study. Before and after the treatment, subjects performed graded exercise test on cycle ergometer and photonic assays for antioxidant scores. At a work load of 100W, 150W or 200W, RER were reduced significantly by 27%, 31%, & 36% (p<0.001), and blood lactate by 14%, 31% & 33%, and also reduced by 24% & 20% immediately and 3 min after exercise (p<0.05). VO2 peak, HR and O2 pulse were not changed in these elite athletes. Carotenoids antioxidant scores were increased by 21% (p=0.02). In conclusion, our data suggest benefits of CM‐LP in improving antioxidant capacity and exercise metabolisms to enhance endurance capability and reducing risks of exercise injury in Chinese elite athletes.
Exercise training preserved myocardial integrity and reduced caspase‐3 activation in acute pressure overload
Authors: Moreira‐Gonçalves Daniel , Henriques‐Coelho Tiago , Fonseca Hélder , Gonçalves Nádia , Duarte José Alberto , Leite‐Moreira Adelino
Published: June 2021

Cardiac overload is an important stimulus for triggering heart failure (HF). We intended to determine if exercise training modulates the early cardiac adaptation to acute pressure overload (APO), by preventing functional and structural deterioration and caspase‐3 activation. Male Wistar rats were submitted to exercise training or sedentary life style for 14 weeks, being prepared after that period for hemodynamic instrumentation: i) SED+Sham, ii) SED+Band and iii) EX+Band. APO was induced by constricting the descending aorta (60% LVPmax elevation) for 2hours. Samples from cardiac tissue were prepared for Light and Transmission Electron Microscopy, and immunohistochemistry (cleaved caspase‐3). APO significantly affected peak pressure rise and peak pressure fall in left ventricle (LV) from SED+Band when compared to EX+Band. Slowing of LV relaxation was observed in SED+Band. Increased intracellular edema and mitochondrial swelling was present in ventricles of SED+Band. Increased levels of cleaved caspase‐3 were detected in both cardiomyocytes and non cardiomyocyte nuclei in LV from SED+Band. In RV, both loaded groups showed only significant non‐cardiomyocyte staining. Exercise training preserved heart function and structure from the APO. This was also accompanied by a significant reduction in caspase‐3 activation in both cardiomyocyte and non‐cardiomyocyte cells from exercised hearts.
Opposite effects of exercise and dexamethasone on skeletal muscle glucose uptake: Role of AMPK and CaMKII
Authors: Amaral Sandra Lia , de Andrade Louzada Juliana Cavalcante , Dionísio Thiago José , Viscelli Bruno Alvares , Dionísio Evandro José , Bosqueiro José Roberto , Martuscelli Aline Mio
Published: June 2021

Dexamethasone (Dexa) and exercise training (T) induce opposite effects in the skeletal muscle glucose uptake. This study investigated whether physical exercise is effective to attenuate the side effects induced by Dexa on insulin‐independent skeletal muscle glucose uptake. Rats underwent a training period where they were either submitted to a running protocol (8 weeks) or kept sedentary. After this T period, the animals underwent dexamethasone treatment (1 mg/kg per day, i.p., 10 days), concomitant with training. An ipGTT was performed and the area under the glucose curve (AUC) was calculated. Western blot analysis was performed to identify AMPKα2 and CaMKII protein expression in the tibialis anterior (TA) muscle. The AUC was 39% higher for dexamethasone‐treated rats, which was attenuated by T. Dexa significantly reduced AMPKα2 (−49%) and CaMKII (−45%) protein expression in the TA muscle. On the other hand, T significantly increased about 30% both AMPKα2 and CaMKII protein expression. Training completely blocked the reduction of AMPKα2 and also inhibited by 15% the decrease of CaMKII protein expression. These results suggest that T prevented the reductions in AMPKα2 and CaMKII protein expression induced by Dexa in the skeletal muscle. Therefore T may be a good strategy to prevent Dexa‐induced peripheral insulin resistance by improving the insulin‐independent glucose uptake. Financial support: FAPESP
Long‐Term, Aerobic Training Increases Adiponectin Levels in Females, but not Males
Authors: Mujumdar Pooja P , Duerksen‐Hughes Penelope , Firek Anthony , Hessinger David
Published: June 2021

Aerobic training (AT) may increase adiponectin (ADP) levels, but the complex regulation of ADP may be influenced by additional factors such as gender and insulin sensitivity. We first studied the changes in ADP in experienced runners (R; n=12) and beginners (B; n=16) undergoing progressive, long‐term (6 mo) AT. We hypothesized that ADP would increase in both R and B groups, but to different extents. Fasting plasma samples were collected at the beginning and end of the training and analyzed for insulin, glucose, and ADP. ADP increased significantly to similar extents in both R and B groups, but only in females. We studied the effects of insulin sensitivity on ADP levels in a complementary cross‐sectional study using HOMA‐IR scores of <1.8 as insulin‐sensitive (IS) and >2.0 as insulin‐resistant (IR). We hypothesized that ADP levels would be highest among experienced female runners independent of their insulin sensitivity status. Based on the training history, insulin sensitivity, and gender, subjects were separated into 8 different groups. ADP levels in the R‐IS‐F group (n = 10) were significantly higher than those in any other group. Thus, long‐term exercise raises ADP levels in IS females, but not IR females. However, ADP level differences in males appear to be due to insulin sensitivity differences and not long‐term exercise.
A Single Nucleotide Polymorphism (SNP) in Titin (TTN) Decreases Muscle Soreness and Strength Deficits after Eccentric Exercise in Women
Authors: Moeckel‐Cole Stephanie Anne , Zambraski Edward , Gordish‐Dressman Heather , Hoffman Eric , Devaney Joe , Clarkson Priscilla
Published: June 2021

There is significant and unexplained variability in muscle damage indicators following eccentric exercise, differences that might be due to genetic alterations in muscle structural genes. We determined whether SNP rs11693372 in the promoter of TTN was associated with strength loss and muscle soreness following eccentric exercise.

Methods

75 women and 79 men performed 50 eccentric actions of the elbow flexors. Strength was measured pre/post‐exercise, and 4d, 7d and 10d post‐exercise. Soreness was assessed via a visual analog scale at similar time points. Associations were compared between the TTN SNP and strength loss and soreness.

Results

Analyses revealed significant differences in strength loss and soreness between genotypes for women only. Compared to T allele carriers, women possessing the ancestral CC genotype experienced: 1) less strength loss post‐exercise (CC, N=13, −44.8% ± 4.9; CT, N=31, −63.2% ± 3.2; TT, N=31, −55.9% ± 3.2; p<=0.01) and after 4d (CC, −26.0% ± 7.7; CT, −51.4% ± 4.9; TT, −39.9% ± 4.9; p<0.01); and 2) less muscle soreness at 3d (CC, 40.0mm ± 5.9; CT, 54.1mm ± 3.9; TT, 63.9mm ± 3.9; p=0.01) and 4d (CC: 30.2mm ± 6.8; CT: 50.3mm ± 4.4; TT: 51.4mm ± 4.4; p<0.01) post‐exercise.

Conclusions

These observations suggest that, for women, possession of the CC alleles mitigated strength loss and the development of muscle soreness following damaging eccentric exercise compared to T allele carriers.
Voluntary aerobic exercise attenuates oxidative stress‐induced apoptotic signalling in cardiac muscle
Authors: Vainshtein Anna , Hood David A
Published: June 2021

An increase in the production of reactive oxygen species occurs with aging, and the resulting oxidative stress has been associated with apoptosis‐related cardiomyopathy. Recent research has indicated that chronic exercise is protective against mitochondrially‐mediated programmed cell death. To further investigate this in the heart we compared voluntary wheel trained (T, 9 weeks) and untrained (C) animals. Training increased heart weight to body weight ratio, and produced a 54% increase in muscle COX activity. Left ventricle (LV) strips were isolated and incubated in vitro with H2O2 for 4 hours. LV strips were then fractionated into cytosolic and mitochondrial fractions. H2O2 treatment induced increases in JNK phosphorylation, Bax localization to the mitochondria, as well as cytosolic AIF by 73%, 106% and 38% in C animals respectively, all of which were attenuated in T animals. Interestingly, H2O2 induced a 2.5‐fold increase in cofilin‐2 localization to the mitochondria, as well as a 64% increase in cytochrome c release which were unaltered by training. These data suggest that regular exercise can attenuate apoptotic signalling via reduced JNK phophorylation, Bax translocation and mitochondrial AIF release. Thus, endurance exercise training has the potential to reduce oxidative stress‐induced programmed cell death in the heart.
Hypotension‐induced expression of c‐fos in the rostral ventrolateral medulla of lean and obese Zucker rats
Authors: Guimaraes Priscila S , Schreihofer Ann M
Published: June 2021

In obese Zucker rats (OZR) acute decreases in arterial pressure (AP) evoke blunted rises in sympathetic nerve activity (SNA) and heart rate (HR) compared to lean Zucker rats (LZR). We hypothesized that hypotension‐induced activation of neurons in rostral ventrolateral medulla (RVLM), the source of drive for SNA, would be less in OZR vs. LZR. Conscious rats with arterial and venous catheters received hydralazine (HDZ; 6.8–15 mg/kg/2 ml/60s, iv) to reduce AP or saline. After 90 min rats were transcardially perfused with formaldehyde. Baseline mean AP was higher in OZR (n=12) vs. LZR (n=13: 124 ± 2 vs. 114 ± 2 mmHg, P<0.001). HDZ reduced mean AP comparably in LZR and OZR for the 90‐min period. The initial rise in HR was blunted in OZR, but by 5 min the rise in HR was comparable. Immunohistochemistry of brain stem sections to identify activation (c‐Fos expression) of catecholaminergic (tyrosine hydroxylase, TH) and non‐C1 RVLM neurons showed that saline evoked minimal Fos expression. In contrast, HDZ evoked robust Fos expression in RVLM (OZR= 48.8 ± 2.8; LZR= 52.8 ± 2.2 Fos+ nuclei) with a minority in TH+ neurons (OZR=8.28 ± 0.6; LZR= 10.8 ± 1.0). However, there was no difference between OZR and LZR in counts of c‐Fos+ neurons with or without TH. These results suggest that although OZR may have an attenuated ability to respond to brief changes in AP, their responses to prolonged hypotension are normal. CAPES (1203‐09‐6), NIH (HL086759)
Cell‐selective Expression of Angiotensin Type 1A Receptors In The Rostral Ventrolateral Medulla Of The Mouse
Authors: Chen Daian , Bassi Jaspreet K , Walther Thomas , Thomas Walter , Allen Andrew M
Published: June 2021

Brain angiotensin (AngII) regulates cardiovascular function and fluid and salt homeostasis. One brain site where AngII acts to regulate blood pressure (BP) and sympathetic nerve activity (SNA) is the rostral ventrolateral medulla (RVLM). This brain nucleus contains a population of catecholaminergic (C1) neurons that are critical for regulation of BP. We showed previously that AngII‐mediated excitation of RVLM neurons in adult mice is dependent upon the angiotensin type 1A receptor (AT1AR). In this study, we examine the effects of inducing AT1AR expression specifically in C1 neurons of the RVLM in AT1A−/− mice via viral delivery. In anesthetised AT1A−/− mice (75 μg/g ketamine, 10 μg/g xylazine IP) replication‐deficient lentiviruses, expressing AT1AR or GFP under the control of a catecholamine‐selective promoter were microinjected into the RVLM bilaterally. We show that in RVLM, viral transgene expression only occurred in the catecholaminergic neurons and produced stable expression of AT1R detected by quantitative autoradiography. In further experiments following viral injections, mice were tracheotomised, and BP and SNA recorded. Microinjection of AngII (1 mM, 50 nl) into RVLM of lentiviral AT1A expressing mice increased BP (21±4 mmHg) and SNA. These results establish that activation of the C1 catecholamine neurons of the RVLM causes a sympathetically mediated pressor response.
Telmisartan inhibits sympathetic nerve activity through the reduction of oxidative stress and release of GABA in RVLM of hypertensive rats
Authors: Kishi Takuya , Hirooka Yoshitaka , Sunagawa Kenji
Published: June 2021

Background

We have demonstrated that angiotensin II‐dependent reactive oxygen species (ROS) and ƒÁ‐amino butyric acid (GABA) in the rostral ventrolateral medulla (RVLM) play a major role in regulating sympathetic nerve activity (SNA) in hypertensive rats. The aim of this study was to determine whether oral administration of angiotensin II type 1 receptor (AT1R) blocker, telmisartan, decreases SNA via the reduction of ROS and release of GABA in the RVLM of hypertensive rats.

Methods and Results

We divided stroke‐prone spontaneously hypertensive rats (SHRSP), as a hypertensive model with enhanced SNA, into 2 groups, telmisartan‐group (TLM) and hydralazine‐group (HYD). Telemetered mean blood pressure (MBP) was reduced in both groups to a similar level. SNA and heart rate (HR) were significantly decreased in TLM, whereas increased in HYD. ROS in the RVLM were significantly lower in TLM than in HYD. The release of GABA measure by microdialysis was significantly higher in TLM than in HYD (15.1±0.7 vs 8.2±1.1 pmol/sample, n=5 for each, P<0.01). Microinjection of angiotensin II into the RVLM increased MBP and HR, and decreased GABA in the RVLM in HYD to a greater extent than in TLM.

Conclusion

Telmisartan decreases AT1R‐dependent ROS and increases GABA in the RVLM, thereby decreases SNA as well as blood pressure in SHRSP.
Angiotensin (1‐7) into rostral ventrolateral medulla is enhanced in spontaneously hypertensive rats
Authors: Nakagaki Toshiaki , Hirooka Yoshitaka , Ito Koji , Hoka Sumio , Sunagawa Kenji
Published: June 2021

Background

Angiotensin‐(1‐7) (Ang‐(1‐7)) is recognized as an important mediator of renin angiotensin system. Ang‐(1‐7) is a peptide of ligand for Ang‐(1‐7)‐Mas receptor, and has opposite actions of angiotensin II in the vasculature. In the central nervous system, however, it has been shown that microinjection of Ang‐(1‐7) into rostral ventrolateral medulla (RVLM), one of vasomotor centers of brainstem increased blood pressure in normotensive rats. The aim of the present study was to determine the possible involvement of Ang‐(1‐7) in the RVLM in hypertension.

Methods and Results

In anesthetized Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we microinjected Ang‐(1‐7) (100 pmol) and a Mas receptor antagonist (A‐779: 100 pmol) into the RVLM. Microinjection of Ang‐(1‐7) increased blood pressure in both strains. The changes were, however, significantly greater in SHR than WKY rats (13.3 ± 1.3 mmHg, n=7 vs. 6.6 ± 0.8 mmHg, n=5; p<0.05). In contrast, microinjection of a Mas receptor antagonist (A‐779) deceased blood pressure significantly greater in SHR than WKY rats (‐26.4 ± 1.7 mmHg, n=5 vs. ‐13.7 ± 0.8 mmHg, n=5; p<0.05).

Conclusion

Both exogenous and endogenous Ang‐(1‐7) in the RVLM are enhanced in spontaneously hypertensive rats. The Ang‐(1‐7)‐Mas receptor pathway in RVLM may contribute to the mechanisms of blood pressure elevation in spontaneously hypertensive rats.
Evidence for a depressor action of AT1 receptors in the nucleus of the solitary tract (NTS)
Authors: Dong Ying , Shan Zhiying , Shi Peng , Raizada Mohan K , Sumners Colin
Published: June 2021

The NTS contains angiotensin II (Ang II) type 1 receptors (AT1R) and their levels are increased in spontaneously hypertensive rats (SHR). However, the precise roles of AT1R in this cardiovascular control center are not established. Here we investigated the cardiovascular effects of AAV2‐U6‐AT1R‐shRNA‐mediated knockdown AT1R in the NTS of SHR. Incubation of rat brainstem neurons in culture with this vector (2×1012gc/ml) decreased AT1aR and AT1bR mRNAs levels by 72% and 68% respectively compared with the control vector AAV2‐U6‐SCR‐shRNA. In vivo, microinjection of AT1R‐shRNA or SCR‐shRNA bilaterally into the NTS of 6 week old SHR (n=3 each group), produced no immediate changes in basal mean arterial blood pressure (MAP) and heart rate (HR), recorded via radiotelemetry. Basal MAP was 120.1 ± 2.11 and 120.5 ± 4.95 mmHg respectively in AT1R‐shRNA and SCR‐shRNA‐injected rats, during the light phase. By 44 days after the microinjections, basal MAP was significantly greater (p<0.05) in the AT1R‐shRNA‐injected SHR (Light phase 167.4 ± 13.73 mmHg; Dark phase 180.9 ± 11.90 mmHg) compared with the controls (Light phase 144.3 ± 6.22; Dark phase 154.1 ± 4.36 mmHg). HR was not different between the two groups at any of the time points. Since AT1R‐shRNA is expected to reduce AT1R levels in the NTS, these data suggest that certain of the AT1R within NTS mediate a depressor action of Ang II. Supported by NIH grants HL‐076803 and HL‐033610.
Extracellular ATP excites ischemically sensitive cardiac sympathetic afferents
Authors: Fu Liang‐Wu , Longhurst John
Published: June 2021

Cardiac sympathetic afferents are activated during myocardial ischemia, a complex process that leads to release of a number of mediators including extracellular adenosine 5′‐triphosphate (ATP). Also, ATP can elicit pain in animal models by stimulating somatic sensory nerve fibers. We therefore hypothesized that ATP stimulates ischemically sensitive cardiac afferents. Nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2–T5) in anesthetized cats. Receptive fields of 10 afferents (CV= 0.32–1.77 m/s) were identified in the left ventricle with a stimulating electrode. Five min of myocardial ischemia stimulated all 10 C‐fibers cardiac afferents, increasing their activity from 0.59±0.26 to 2.48±0.42 imp/s. Epicardial application of ATP (0.5–1 μmol), αβ‐meATP (0.2–0.5 μmol), and ADP (0.5–1 μmol) each stimulated 4 cardiac afferents, increasing the activity of these afferents by 356%, 435% and 178%, respectively. Administration of PPADS (30 mg/kg, iv), a P2 receptor antagonist, eliminated the responses of 3 other cardiac afferents to epicardial ATP, αβ‐meATP and ADP. PPADS also attenuated the ischemia‐related increase in activity of 3 separate afferents by 41%. These preliminary data suggest that extracellular ATP contributes to stimulation of cardiac sympathetic afferents during myocardial ischemia through a P2 receptor mechanism. (Supported by NIH HL66217)
Maternal Diabetes (MD) Increases Large Conductance Ca2+‐activated K+ (BK) Currents Which Alter Action Potential (AP) Properties But Do Not Affect Excitability of Parasympathetic Cardiac Motoneurons (PCMNs) In The Nucleus Ambiguus (NA) of Neonatal Mice
Authors: Lin Min , Chen Qing‐Hui , Li Lihua , Wurster Robert D. , Cheng Zixi (Jack)
Published: June 2021

In an accompanying abstract (Lin et al. EB 2010), we have demonstrated that MD increases small conductance Ca2+‐activated K+ (SK) currents which are associated with MD‐induced alteration of AP properties and attenuated excitability of PCMNs. Presently, we test the hypothesis that MD also alters BK currents. Neonatal mice from OVE26 diabetic (Type 1) mothers (NMDM) and normal FVB mothers (control) were used. XRITC was injected into the pericardial sac at P7–9 to label PCMNs. Two days later, XRITC‐labeled PCMNs in slices were identified. Whole‐cell (current and voltage) clamps were used to measure spike frequency, repolarization (half‐width), afterhyperpolarization (AHP), outward currents, and afterhyperpolarization currents (IAHP). Compared to control, we found (p<0.05) that in NMDM that 1) Ca2+‐sensitive transient outward currents and IAHP increased; 2) application of Ca2+‐free solution increased half‐width and decreased AHP amplitude; 3) BK channel blockers ChTX or paxilline‐sensitive transient outward currents and IAHP increased; 4) blockade of BK channels with ChTX or paxilline increased AP half‐width and decreased AHP amplitude at 10 ms, but not at 50 ms; 5) application of ChTX or paxilline does not affect spike firing frequency in response to current injections in both control and NMDM. In contrast to SK channels, we suggest that MD increases BK currents which contribute to altered AP properties, but do not directly affect the attenuated excitability of PCMNs in NMDM. NIH R01 HL79636.
Impact of maternal diabetes on short and long‐term renal injury in the offspring
Authors: Maric Christine , Roach Lauren , Haggerty Deani , Richard Ashley , Marbury David Caleb , Alexander Barbara T
Published: June 2021

Studies suggest that maternal diabetes and the immediate postnatal environment may confer increased susceptibility to cardiovascular and renal risks later in life. The present study investigated the influence of maternal diabetes and the postnatal environment on blood glucose and albuminuria in the offspring of non‐diabetic (ND) and streptozotocin (STZ)‐induced diabetic rats (D). The study also included a group in which the offspring was cross‐fostered on postnatal day 2 (offspring of ND mothers given to D mothers and vice versa). Blood glucose and urine albumin excretion (UAE) were measured weekly for 4 months. Up to postnatal day 16, offspring of D mothers had a 30% increase in blood glucose compared with offspring of ND mothers (ND, 127±5; D, 167±10 mg/dl; P<0.05), while after weaning, blood glucose levels were similar to that in ND. At 4 months of age, offspring of D mothers showed a 50% increase in UAE (ND, 0.4±0.1; D, 0.6±0.2 mg/day, P<0.01). In contrast, no differences in blood glucose levels were observed in the offspring of D mothers that were cross‐fostered to ND mothers after birth and these cross‐fostered animals did not develop albuminuria at 4 months of age. Studies are ongoing to measure blood pressure and renal function in these animals. Our data suggest that both exposure to a diabetic milieu in utero and the immediate postnatal environment play an important role in development of renal disease later in life.
Effect of L‐arginine supplementation on renal morphology of rats submitted to unilateral ureteral obstruction.
Authors: Gomes Guiomar Nascimento , Pletiskaitz Thais Maria , Carraro‐Lacroix Luciene Regina , Gil Frida Zaladek
Published: June 2021

This work was designed to study the effect of L‐Arginine (Arg) treatment on renal morphology changes after unilateral ureteral obstruction (UO). Ureteral obstruction was performed by ligation of the left ureter of Male Wistar rats, 3 month old. Four experimental groups were studied: control‐sham operated: C; obstructed: UO; control treated with Arg: CA; obstructed treated with Arg: UOA. Groups CA, and UOA received as drinking water a solution containing arginine 1% and sucrose 1%, since 24 hours before surgery until 14 days of obstruction, when the animals were studied. The groups C and UO received 1% sucrose solution. We studied: glomerular morphology, alpha smooth muscle actin (α‐SMA) expression, macrophage infiltration (ED1), proliferating cell nuclear antigen (PCNA) expression and fibrosis. We observed that 14 days after UO, α‐SMA expression and macrophage infiltration (ED1) were increased in UO kidney. In OUA, both α‐SMA expression and ED1 presence were reduced. Glomerular hypertrophy was observed in contralateral kidney from UO rats. The treatment with Arg also reduced this response. These results indicate that L‐arginine supplementation has a beneficial effect on renal morphological changes caused by ureteral obstruction.

Supported by FAPESP, CAPES, CNPq.
Induction of Hypertrophic Growth and Remodeling in the Kidneys of Guanylyl Cyclase‐A/Natriuretic Peptide Receptor‐A Gene‐disrupted Null Mutant Mice
Authors: Das Subhankar , Au Edward , Krazit Stephen T , Pandey Kailash N.
Published: June 2021

Systemic disruption of guanylyl cyclase‐A/natriuretic peptide receptor‐A (GC‐A/NPRA) gene (Npr1) has been shown to increase blood pressure, marked cardiac hypertrophy, and renal insufficiency in mice. The objective of the present study was to evaluate the consequences of Npr1 gene‐disruption on renal inflammation, collagenesis, and remodeling in null mutant mouse model. This study was performed utilizing the adult (24‐weeks of age) male Npr1 gene‐disrupted (Npr1−− 0‐copy) and wild‐type (Npr1+/+; 2‐copy) mice. The results showed that systemic disruption of Npr1 gene causes an increased renal tubular damage characterized by its dilation with flattened epithelium and expanded interstitial spaces in Npr1−/− (0‐copy) null mutant mice compared with Npr1+/+ (2‐copy) mice. Furthermore, a significant increase occurred in pro‐inflammatory cytokines including tumor necrosis factor‐alpha (TNF‐α; 4‐fold) and interleukin‐6 (IL‐6; 4.5‐fold). A decreased level of matrix metalloproteinase‐9 (MMP‐9) and increased level of collagen was observed in the 0‐copy mice kidney compared with wild‐type control mice kidney. Thus, the present results indicate that the disruption of Npr1 gene causes a significant increase in the synthesis of pro‐inflammatory cytokines and collagen in the kidney of Npr1 null mutant (0‐copy) mice, suggesting a critical role of Npr1 gene in renoprotection and prevention of kidney damage and remodeling in hypertensive disease state.
Induction of heme oxygenase‐1 protects methyl mercury‐caused cytotoxicity in cultured mouse mesangial cells
Authors: Suh Chang Kook , Cha Seok Ho
Published: June 2021

The kidney is a major target organ for many trace metals, and it has been shown that many of these metals have the ability to change heme metabolism in kidney. HO‐1 is known to be induced by heavy metals, UV light, heme and so on. Among these heavy metals, mercury and methyl mercury (MeHg) are environmental toxins that cause severe neurological and renal complications in humans and experimental animals. Methyl mercury is considered a more toxic compound to mercuric chloride. Therefore we investigated the relationship between MeHg‐caused cytotoxicity and HO‐1 expression using molecular biological techniques in cultured mouse mesangial cells. The expression levels of HO‐1 mRNA and protein were increased by the treatment of MeHg, with dose‐ and time‐dependent manner. The increased HO‐1 expression was attenuated by the treatment of actinomycin D, an inhibitor of transcription, but no expressional change induced by MeHg was observed by the treatment of zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits HO activity. In cell viability test using MTT assay, MeHg‐induced cytotoxicity was increased time‐dependently. This MeHg toxicity was enhanced by the treatment of ZnPP. These results show HO‐1 induction takes part in protection to MeHg toxicity in cultured mouse mesangial cells.
Ginger (Zingiber officinale ) ameliorates metalexyl fungicide induced kidney damage in albino mice
Authors: Lamfon Hawazen Ahmad , Sakr Saber A
Published: June 2021

The work extends to study the possible role of the aqueous extract of Ginger (Zingiber officinale) in minimizing the toxicity of metalaxyl. Animals were divided into 4 groups. Group 1: given metalaxyl at a dose level of 1/10 LD50 for 4 weeks, Group 2: given metalexyl and ginger, Group 3: given ginger and Group 4: controls. Histopathological and biochemical observations of the kidney functions parameters and oxidative enzymes were carried out. Kidney cortex of metalexyl‐treated mice showed many histopathological alterations. Metalexyl caused marked elevation in serum creatinine and blood urea nitrogen. Moreover, metalaxyle administration to animals significantly increased malondialdehyde and decreased superoxide dismutase (SOD) and catalase activity. Treating animals with metalexyl and ginger led to an improvement in the histological structure of the kidney together with significant decrease in urea and creatinine. Moreover, ginger reduced the level of serum malondialdhyde and increased the serum level of antioxidant enzymes, SOD and catalase. The results indicated that ginger had ameliorative effect against kidney damage induced by metalexyl and this may be mediated by its potent antioxidant activities. The present work is supported by Umm Al‐Qura University and Menoufia University.