bluuebunny/crossref_metadata_2025_split huggingface dataset:
PGC‐1α – Dependent TFEB Expression and Activation with Exercise
Authors: Erlich Avigail Tamar , Brownlee Diane , Beyfuss Kaitlyn , Hood David 
Published: November 2023

A functional mitochondrial network is required for the maintenance of healthy skeletal muscle, and this is controlled by the opposing processes of mitochondrial biogenesis and mitophagy. The coactivator PGC‐1a regulates the synthesis of new mitochondria, while the coordinated transcription of lysosomal and autophagy‐related genes is controlled by transcription factor EB (TFEB). PGC‐1a activation and expression are induced with exercise, leading to a subsequent increase in mitochondrial biogenesis. However, the effect of exercise on TEFB expression and activation has yet to be elucidated. Since biogenesis and mitophagy are closely linked, the purpose of our study was to investigate the interplay between PGC‐1a and TFEB in maintaining mitochondrial homeostasis in response to chronic contractile activity in C2C12 myotubes, and following acute treadmill exercise in WT and PGC‐1a KO mice. In C2C12 cells, TFEB nuclear localization was increased by 1.6‐fold following 2 hours of acute, electrical stimulation‐induced contractile activity. Cells transfected with a 1600 bp TFEB promoter‐reporter construct revealed that TFEB transcription was simultaneously increased by 3‐fold by contractile activity. To evaluate this in vivo, WT and KO mice were subjected to acute treadmill exercise. In WT mice, TFEB translocation to the nucleus increased 2.4‐fold. In contrast, KO mice exhibited no increases in TFEB translocation with exercise, yet showed a 4‐fold increase in mTOR activation. This suggests an increased phosphorylation and inhibition of TFEB in KO muscle following exercise. In addition, TFEB transcription, assessed through the intramuscular electroporation of the TFEB promoter‐reporter construct, was elevated by 4‐fold in response to exercise. This transcriptional response to exercise was completely abolished in the KO mice. TFEB protein levels were also reduced by 30% in the KO mice compared to their WT counterparts, however no changes were observed in most of the downstream targets of TFEB transcription. mRNA levels of the mitochondrial marker COXI were reduced by 47% in KO mice compared to WT counterparts basally, while exercise induced a 33–38% elevation in both genotypes. Furthermore, both WT and KO mice exhibited and 50% decrease in the mRNAs encoding autophagy genes. Our data suggest that acute exercise provokes TFEB expression and activation both in vitro and in vivo, in a PGC‐1a‐dependent manner. PGC‐1a controls expression of TFEB with exercise likely via transcriptional mechanisms. Furthermore, ablation of PGC‐1a seems to play a role in increased TFEB inhibition via mTOR phosphorylation, indicating a more complex role for PGC‐1a in mediating TFEB expression, as well as function.Support or Funding InformationThis work is supported by the Natural Science and Engineering Research Council (NSERC) of Canada.
Linear and Nonlinear Analysis of Heart Rate Variability in an Experimental Model of Diabetes and Obesity Submitted to Myocardial Infarction: Role of Aerobic Exercise Training
Authors: Conti Filipe F , Sartori Michelle , Santos Fernando , Dias Danielle S , Machi Jacqueline F , Souza Leandro E , Jensen Leonardo , Morris Mariana , Irigoyen Maria‐Claudia , De Angelis Kátia 
Published: November 2023

This study was designed to verify the effects of aerobic exercise training (ET) on cardiac autonomic modulation in an experimental model of diabetes and obesity submitted to myocardial infarction. Ob/ob mice (10 weeks old) were randomized into (n=7): sedentary (S), myocardial infarction sedentary (MIS) and myocardial infarction + ET (MIT) groups. Myocardial infarction was induced by coronary artery occlusion. Aerobic exercise training was performed in treadmill (5x/week, 8 weeks, 40–60% maximal test). RR interval was recorded in awake animals at the end of the protocol. Cardiac autonomic modulation was evaluated by linear and nonlinear analysis of heart rate variability. At the beginning of the protocol, the groups submitted to myocardial infarction (MIS and MIT) presented lower exercise capacity in relation to the S group (S: 9.9±0.2 vs. MIS: 6.4±0.7; MIT: 4.5±0.6 min). Myocardial infarction promoted a drastic reduction of vagal modulation evidenced by linear analysis: RMSSD index (S: 5.9±0.7 vs OIS: 0.7±0.1 ms), standard deviation of pulse interval (S: 11.5±1.8 vs MIS: 1.4±0.2 ms) and high frequency band of pulse interval (S: 8.8±2.0 vs MIS: 0.1±0.05 ms2); as well as by nonlinear analysis: SD1 (S: 4.2±0.5 vs MIS: 0.5±0.1 ms). On the other hand, at the end of the protocol, the trained group (MIT) presented higher exercise capacity, while the sedentary groups (S and MIS) showed lower exercise capacity when compared to their initial values (S: 8.6±0.4; MIS: 4.3±0.5; MIT: 7.8±0.5 min). The aerobic exercise training was able to prevent these cardiac vagal dysfunctions observed in the MIS group, showing higher values for RMSSD index (MIT: 2.8±0.7 ms) and SD1 (MIT: 2.0±0.5 ms) when compared to the MIS group. Altogether, the results showed that the myocardial infarction led to a severe reduction of vagal modulation and the aerobic exercise training presented positive effects preventing this severe reduction.Support or Funding InformationCAPES (99999.008874/2014‐00); CNPq, FAPESP and UNINOVE
Muscle Recruitment Patterns Above Critical Power
Authors: Alexander Andrew M , Hammer Shane M , Didier Kaylin D , Baumfalk Dryden R , Barstow Thomas J 
Published: November 2023

Critical power (CP) represents an exercise intensity that above which exercise tolerance is limited and can be predicted. As the muscle fatigues during constant‐load exercise above CP, muscle motor unit recruitment is increased to meet the exercise demand. Our laboratory has shown that at task failure in small muscle mass handgrip exercise, muscle recruitment is not different across exercise intensities above CP.PurposeTo test the hypotheses that 1) end‐exercise muscle recruitment is not intensity‐dependent during whole body exercises above CP, and 2) at exercise intensities above CP muscle recruitment does not reach steady state, but continuously increases until task failure occurs.MethodsTo date, four healthy, young men (23.5 ± 2.0 yrs; 92.6 ± 4.2 kg, 175 ± 4 cm) completed five exercise bouts to task failure on separate days. During the first session, subjects performed an incremental test on a cycle ergometer to determine peak power (Ppeak). The subjects then performed four constant load cycle tests on subsequent days. The power outputs during the constant load tests were selected to elicit task failure within the pre‐determined time range of 2–15 min to ensure all tests were above CP. Electromyography (EMG) was measured on the L vastus lateralis to quantify potential increases in muscle recruitment and were reported as 20 contraction averages.ResultsAverage Ppeak was 300 ± 31 W. Work rate at which CP occurred was 178 ± 17W (59.4% ± 2.3 % Ppeak). There were no significant differences in end‐exercise iEMG (p=0.078) among exercise intensities above CP. Further, for each exercise intensity all subjects demonstrated a progressive increase in iEMG until task failure.ConclusionsConfirming our hypotheses, the current data suggest that during cycling exercise above CP, muscle recruitment at task failure is similar across exercise intensities.
Whole Body Hyperthermia Enhances Angiogenesis in Tenotomized Rat Skeletal Muscle
Authors: Hirunsai Muthita , Srikuea Ratchakrit 
Published: November 2023

In response to disuse, skeletal muscle is characterized by a reduction of fiber size, increase of intramuscular fibrosis, and regression of capillaries. Hyperthermia has been known to alleviate muscle atrophy and remodel extracellular matrix. Of these, the mechanisms underlying the beneficial effects of heat treatment on capillary adaptation following disuse atrophy are unknown. In the current study, we examined the effects of hyperthermia on angiogenesis and expression of the angiogenic factors in the soleus muscle following Achilles tendon ablation (tenotomy). Male Wistar rats were randomly assigned into three groups: control (CON), tenotomy for 8 day without heat treatment (TEN), and tenotomy for 8 day plus heat treatment (TEN+HEAT). Whole body hyperthermia was maintained at 40.5–41.5°C for 30 min, 24 h before and after tenotomy, and continued for five consecutive days. Following tenotomy, soleus muscle revealed a reduction in muscle fiber size and a remarkable loss of intramuscular capillary. These occur accompanied with decrease in vascular endothelial growth factor receptor‐2 (VEGFR‐2), the pro‐angiogenic factor and increase in thrombospondin‐1 (TSP‐1), the anti‐angiogenic factor, protein expressions in soleus muscle. However, tenotomy had no effect on the protein expression of vascular endothelial growth factor (VEGF). To rescue the capillary loss, whole body hyperthermia preserved the level of capillarization associated with increased VEGFR‐2 and reduced TSP‐1 protein expressions in tenotomized soleus muscle. Whereas, hyperthermia had no additional effect on VEGF protein level in soleus muscle after tenotomy. Collectively, whole body hyperthermia mitigated the effect of tenotomy‐induced capillary regression, in part, by modulating the angiogenic regulators. The results from this study suggest the potential therapeutic effect of heat treatment in relieving intramuscular capillary regression during skeletal muscle atrophy.Support or Funding InformationThe research was supported by grant from Srinakharinwirot University.
Identification of a Novel Regulator of Vasopressin Secretion
Authors: Stein Lauren Michelle , Soo Jasmine , Loewen Spencer , Hindmarch Charles , Ferguson Alastair , Yosten Gina , Samson Willis 
Published: November 2023

We identified a novel hypothalamic peptide, Phoenixin, and demonstrated its hypothalamic and pituitary actions to control reproductive hormone secretion (Yosten et al. J Neuroendocrinol 25:206, 2013). We now have identified the orphan G protein‐coupled receptor, GPR173, to be the cognate receptor for Phoenixin (Stein et al. Am J Physiol 311:R489,2016). Transient compromise of either GPR173 or Phoenixin production in rat hypothalamus significantly interrupted estrous cyclicity, suggesting that this ligand‐receptor pair is essential for normal reproductive function. In situ hybridization histochemistry studies revealed that Phoenixin is expressed in neurons of the paraventricular (PVN) and supraoptic (SON) nuclei, as is GPR173. We hypothesized that in addition to its action to control reproductive physiology, Phoenixin acts in PVN and SON to control vasopressin (AVP) or oxytocin (OT) secretion. Hypothalamo‐neurohypohysial (HNS) explants released AVP but not OT in response to Phoenixin. Intracerebroventricular administration of Phoenixin into conscious, unrestrained male rats significantly increased circulating AVP, but not OT, levels in plasma. Bath application of Phoenixin in hypothalamic slice preparations resulted in depolarization of PVN neurons indicating a direct, neural action of Phoenixin in hypothalamus. Our results suggest that the newly described, hypothalamic peptide Phoenixin, in addition to its effects on hypothalamic and pituitary mechanisms controlling reproduction, may play an important role in the regulation of fluid and electrolyte homeostasis.Support or Funding InformationSLU President's Research Fund
Hepatic Androgen Receptor Modulates Hyperandrogenemia‐induced Glucose Metabolic Dysfunction and Hepatic Insulin Resistance
Authors: Andrisse Stanley , Wu Sheng 
Published: November 2023

Hyperandrogenemia (HA) has been shown to cause impaired glucose tolerance and insulin resistance in women and in female rodent models. The mechanism of this HA‐induced metabolic dysfunction is not fully understood. We developed a mouse model that displayed pathophysiological serum androgen levels with normal body mass to ensure that the phenotypes were directly from androgens and not an indirect consequence of obesity. DHT mice demonstrated impaired glucose, insulin and pyruvate tolerance, and lowered hepatic insulin action. Our previous findings have shown that the liver is a primary target of HA‐induced metabolic dysfunction. The goal of this study was to determine the role of hepatic androgen receptor (AR) in DHT‐induced impaired glucose tolerance and hepatic insulin resistance. Molecular (Western blots, qRT‐PCR, immunoprecipitation (IP), and chromatin IP) assays were performed on the liver tissue samples obtained from the low dose DHT and control mice. Additionally, a low dose DHT cell model using H2.35 female mouse hepatocytes was developed to study androgen and AR effects on insulin signaling. Low dose DHT lowered hepatic insulin stimulated phosphoinositide‐3‐kinase (PI3K) activity, p‐AKT and p‐FOXO1 but had no effect on p‐Y‐IRS1/2 compared to control. Mechanistically, DHT increased hepatic AR binding to PI3K‐p85 resulting in dissociation of PI3K‐p85 from PI3K‐p110 leading to reduced PI3K activity and decreased p‐AKT, thus lowered insulin action. In addition, DHT increased gluconeogenesis via AR‐specific transcriptional upregulation of gluconeogenic enzymes (G6Pase and PEPCK) and co‐activators (FOXO1 and CREB). In the cell model, the DHT‐induced hepatocyte insulin resistance and increased gluconeogenesis was reversed by AR antagonist, flutamide. These findings suggest that AR in the liver is a key driver of HA‐induced whole body and hepatic metabolic dysfunction and insulin resistance. AR acts both in the nucleus and the cytosol to enact these detrimental effects on metabolism.Support or Funding InformationNIH grant 5R00HD068130‐05 awarded to SW. JHU's Provost's Postdoctoral Diversity Fellowship awarded to SA.
Renal Olfactory Receptor 1393 May Contribute to the Progression of Diabetic Nephropathy
Authors: Shepard Blythe D , Pluznick Jennifer L 
Published: November 2023

Olfactory receptors (ORs) are G protein‐coupled receptors which serve to detect odorants in the nose. It is now appreciated that ORs also have roles beyond odorant detection and serve as important chemosensors in a number of tissues including the kidney. We recently found (Shepard, et al Sci Rep 2016) that one of these renal ORs, Olfr1393, localizes to the apical membrane of the proximal tubule where it plays a role in renal glucose handling. Whole‐animal Olfr1393 knockout (KO) mice present with mild glycosuria and improved glucose tolerance despite being euglycemic with normal insulin levels. Examination of the Na+/glucose co‐transporters (Sglt1 and Sglt2) revealed a 22% decrease in the luminal localization of Sglt1, but not Sglt2, despite similar total protein expression, implicating Olfr1393 as a novel regulator of renal Sglt1. The Sglts have recently emerged as therapeutic targets for patients with diabetes and have been shown to attenuate the progression of diabetic nephropathy and diabetes‐induced hyperfiltration due to increased distal Na+ delivery. Given Olfr1393's role as a regulator of Sglt1, in this study we sought to investigate the contribution of Olfr1393 to the progression of diabetic hyperfiltration. Olfr1393 WT (n = 4) and KO mice (n = 9) were challenged with a high fat (HF) diet (60% kcal) for 16 weeks and glomerular filtration rate (GFR; transcutaneous measurement of FITC‐Sinistrin clearance) and glucose and insulin tolerance were measured. Upon the switch to a HF diet, both WT and KO mice consistently gained weight and after 16 weeks there were no differences in the kidney weight:body weight ratio, fasting blood glucose or response to glucose and insulin tolerance tests. To track diabetes‐induced hyperfiltration, GFR was measured after 0, 11.5 and 16 weeks on diet. As expected, by 16 weeks on diet WT mice presented with diabetes‐induced hyperfiltration (GFR/BW week 0 – 233ml/min; week 16 – 576ml/min, P=0.00009)). However, this hyperfiltration was blunted in the KO mice (GFR/BW week 0 – 277ml/min; week 16 – 435ml/min; P=0.005 (KO week 0 vs. KO week16), P=0.09 (Week 16 WT vs KO). Finally, in preliminary data, using Oil Red O lipid staining we detected a trend toward reduced lipid accumulation in the livers of Olfr1393 KO mice (n = 2) compared to a WT littermate (n = 1). Taken together, these data indicate that Olfr1393, through its regulation of Sglt1, contributes to the progression of diabetic nephropathy which may have extra‐renal consequences.Support or Funding InformationNIDDK
Involvement of Serotonergic Neurons in the Ventilatory Response to Hypercapnia in Birds (Chicken, Gallus gallus)
Authors: Santos Kassia M , Abreu Sheila B , Garcia Giuliana Milan Andrade , Bícego Kenia C , Gargaglioni Luciane H , da Silva Glauber S F 
Published: November 2023

Respiratory system regulates acid‐base balance by eliminating carbon dioxide (CO2), with PCO2/pH variations detected mainly by central chemoreceptors. In mammals, serotonergic neurons (5‐HT) have been demonstrated to play a crucial role in the ventilatory response to CO2. It is known that birds have central CO2/pH chemoreceptors and that 5‐HT neurons are organized in the raphe. However, it is not known the neuronal phenotype involved in central chemoreception in birds. We hypothesized that 5‐HT neurons play a role in the central CO2/pH chemoreception in birds. Therefore, the present study aimed to verify the involvement of 5‐HT neurons in respiratory control in chicken (Gallus gallus) exposed to hypercapnia. Five‐day old male chicks were submitted to surgical procedures and 1μl of anti‐SERT‐SAP immunotoxin (0.1mM) was microinjected into the fourth ventricle for specific deletion of 5‐HT neurons. The control group received IgG‐SAP injections. Animals underwent to hypercapnia exposure (7% CO2) ten days after surgery. Pulmonary ventilation (VE; barometric method, whole body plethysmography) and body temperature were measured. Brainstem 5‐HT lesion was verified by immunohistochemistry. Both groups (control and lesioned) augmented VE during hypercapnia. Ventilatory response to hypercapnia of lesioned chickens was attenuated by ~30% compared to the control animals [mean values of VE during hypercapnia: 2429 and 1805 ml/kg/min, control vs lesioned group, respectively; P<0.05, (n=6)]. The attenuated response to hypercapnia was due to the lower respiratory frequency (77 and 59 breaths/min, control vs lesioned group, respectively. P<0.05). The results suggest that brainstem serotonergic neurons contribute to the respiratory response to CO2 in chicken, playing an excitatory role in CO2‐drive to breathing.Support or Funding InformationSao Paulo Research Foundation (FAPESP)
Respiratory Control in a Rat Model of Alzheimer's Disease (TgF344‐AD)
Authors: Murphy Kevin H. , Burns David P. , Barry‐Murphy Kevin , Rae Mark G. , O'Halloran Ken D. , Lucking Eric F. 
Published: November 2023

Synaptic defects seen in tauopathies such as Alzheimer's disease (AD) are known to result in the impaired function of major brain networks. It is plausible to consider that such changes can directly or indirectly affect central respiratory networks within the brainstem with consequences for respiratory homeostasis. Alzheimer's patients display indicative signs of oro‐pharyngeal complications and sleep‐disordered breathing. Upper airway dysfunction has also been shown to develop and persist in animal models of AD. The aim of this study was to characterise respiratory control at an early stage of disease progression in a novel rat model of AD.We utilised a transgenic (Tg) rat model of AD (TgF344‐AD), which expresses the mutant human transgenes: amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9). Tg (male n=9; female n=12) and non‐transgenic wild type (non‐Tg; male n=8; female n=7) animals (34–49 weeks) were studied using whole‐body plethysmography to determine ventilation and metabolism. Cardiorespiratory reflex responses to chemostimulation were subsequently determined in a subset of animals under urethane anaesthesia (1.5g/kg). Data were statistically compared by 2‐way ANOVA (genotype × sex) with Bonferroni post hoc tests.Transgenic mutation did not significantly alter baseline minute ventilation (VE; p>0.05) however, sex‐specific differences in breathing were evident. Exposure to 10 minutes of hypoxia (FiO2 =0.1) manifested a greater VE response in females compared with males (p<0.01); however, the ventilatory response to hypoxia was equivalent in Tg animals compared with non‐Tg animals. Similarly, baseline data recorded under anaesthesia revealed that VE was equivalent in Tg and non‐Tg animals (p>0.05) and consistent with data derived from plethysmography, sex differences in breathing were evident. No genotype or sex difference was observed in diaphragm integrated EMG activity for peak amplitude, area under the curve and maximum slope analysis (p>0.05). Baseline mean arterial pressure (MAP) was equivalent in Tg and non‐Tg animals (p>0.05), although females had a significantly increased MAP compared with males (p<0.01).In conclusion, expression of human transgenes in this AD animal model did not significantly alter respiratory behaviour. Further analysis of respiratory stability and respiratory EMG responses to chemostimulation and airway obstruction will be carried out.Support or Funding InformationDepartment of Physiology, University College Cork, Cork, Ireland
The Klebsiella pneumoniae Gene ytfL Triggers Microtubule Disassembly in Lung Epithelial Cells through KATNAL1
Authors: Chua Michael Dominic , Siu L Kristopher , Yeh KuoMing , Guttman Julian Andrew 
Published: November 2023

The Gram‐negative bacterium Klebsiella pneumoniae can cause septicemia, pneumonia, liver abscesses, and meningitis resulting in mortality rates as high as 44%. Unfortunately, the sub‐cellular interactions of these bacteria with host cells remain poorly understood. Because many bacterial pathogens target the host cell cytoskeleton, we examined the host cell cytoskeleton of K. pneumoniae‐infected lung epithelial cells. In this study, we focused on the host microtubule network and found that microtubules were severed by the microbes, which ultimately led to the disassembly of the entire microtubule network. Because severing of microtubules in lung epithelial cells are regulated by host cell mechanisms, we hypothesized that a K. pneumoniae gene product would trigger the microtubule severing events through the activation of a host microtubule severing protein. To test this hypothesis, we screened the known disease‐causing proteins of K. pneumoniae and found that expression of the capsular polysaccharide, outer membrane porins, and the type VI secretion system were not important for inducing microtubule severing. Next, we constructed and screened a library encompassing essentially all (~3000) K. pneumoniae genes to identify genes that could cause this phenotype. Using this library, we identified the gene KP ytfL that caused the microtubule severing phenotype. To further characterize this novel mechanism, we immunolocalized all known epithelial cell microtubule severing proteins in K. pneumoniae‐infected cells and found that the katanin‐like protein 1 (KATNAL1) localized precisely to the sites of microtubule severing. Taken together, our study shows that K. pneumoniae exploits a novel strategy to disassemble epithelial cell microtubules during its infections. The disassembly of microtubules is initiated by the expression of the bacterial gene KP ytfL, which ultimately induces the host protein KATNAL1 to sever microtubules and disrupt the microtubule network of host cells.Support or Funding InformationThis study was funded by NSERC, Taiwan NHRI and SFU Funds.