bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dapagliflozin Stimulates Renal Ammonia Excretion in Rats
Authors: Silveira Isabela Borges , Lichtenecker Debora CK , Gomes Guiomar N 
Published: May 2024

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs that induce glycosuria and are used to treat type 2 diabetes mellitus, moreover it has also been used in other conditions such as heart failure and atherosclerosis. However, little is known about the effects of these drugs on renal function. Considering that the maintenance of acid-base balance is closely related to renal physiology, in this study we evaluated the influence of chronic use of dapagliflozin on global renal function and urinary excretion of ammonia and titratable acids. Objective: To evaluate global renal function and urinary acid excretion (ammonia and titratable acid) in male Wistar rats chronically treated with dapagliflozin. Methods: 3-month-old male Wistar rats were randomized to control (C) and dapagliflozin (D) groups. Animals in group D received dapagliflozin (3 mg/kg, gavage) for 4 weeks. All animals were given food and water ad libitum throughout the experimental protocol. At 4 months of age, animals were placed in metabolic cages for 24-hour urine collection followed by blood sampling. Plasma concentrations of creatinine, sodium, potassium, urea, pH, pCO2, and bicarbonate were evaluated. The following were also evaluated: body weight, water intake, urine flow, and excretion of ammonia, titratable acids, glucose, and protein. Protocol approved by CEUA-UNIFESP number: 5985180423. Values expressed as mean ± standard error; number of animals per group: 6. Results: No significant changes were observed in blood gas parameters: pH (C: 7.33±0.043; D: 7.36±0.027), pCO2 (C: 53.30±2.40; D: 52.67±3.63 mmHg) and HCO3− (C: 27.07±1.31; D: 29.75±1.72 mEq/L) and no significant changes in plasma creatinine concentration (C: 0.41±0.04; D: 0.40±0.04mg/dl), Na+ (C: 144±0.47; D: 137±2.04 mmol/l) and K+ (C: 4.30±0.21; D: 4.16±0.20 mmol/l). We observed a significant increase in urine flow (C: 0.027±0.006; D: 0.068±0.005 mL/min/kg), possibly associated with intense glycosuria (C: 0.017±0.005; D: 8.97±0.51 g/24h). The significant increase in plasma urea concentration (C: 39.17±2.57; D: 48.83±1.27 mg/dL) and proteinuria (C: 11.04±0.30; D: 15.79±0.56 mg/24h) may indicate some renal impairment. Considering the marked increase in urinary excretion of ammonia (C: 0.65±0.05; D: 3.49±2.31 mEq/24h) and titratable acids (C: 0.180±0.036; D: 0.628±0.078 mEq/24h), we can conclude that the drug-induced glycosuria may lead to biochemical adaptations to maintain blood glucose levels within the normal range, at the expense of increased metabolic acid production. However, further experiments are needed to confirm this hypothesis. CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Enhanced Functional Ultrasound Imaging for Longitudinal Cerebrovascular Assessment in Aging Mouse Models
Authors: Tarantini Stefano , Negri Sharon , Nyúl-Tóth Ádám , Sanford Madison , Reyff Zeke , Ballard Cade , Yabluchanskiy Andriy 
Published: May 2024

This study aims to enhance the visualization of deep cerebrovascular structures and blood flow in the aging brain, a key factor in understanding the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). We hypothesized that functional ultrasound (fUS) imaging through a polymethylpentene window could provide high-resolution insights into cerebral blood flow (CBF) in older mice. Employing this method, we replaced the skull of elderly (24-month-old C57BL/6) mice with a transparent window, allowing for consistent, non-invasive fUS imaging over time. We utilized ultrasound localization mapping (ULM) with a microbubble (approximately 10 micrometers (μm)) suspension for detailed mapping of microvascular vessels and flows. Data were analyzed using a FIJI-based platform to interpret high-quality ULM images. Our results demonstrate this novel method's effcacy in revealing intricate vascular details, proving its utility for longitudinal CBF assessments in physiological research in preclinical murine models and aging. This study was supported by the following funding sources: NIH R03AG070479, K01AG073614, R21AG080775, American Heart Association, Hevolution/AFAR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Impact of the Estrous Cycle on Abdominal Pain
Authors: Bennett Aidan , Baker Corey , Alward Taylor , Vanner Stephen , Reed David , Lomax Alan 
Published: May 2024

Background: Irritable bowel syndrome (IBS) is a chronic abdominal pain disorder that affects women twice as often as men. While luminal mediators of both host and bacterial origin have been implicated in modulating abdominal pain in IBS patients, gonadal hormones have also been shown to influence pain signaling. Estrogen has been identified as a pronociceptive mediator that can modulate central and peripheral neural pathways. Given this, we hypothesized that the estrous cycle modulates sensory neuronal excitability, thereby altering the sensitivity to luminal mediators and this contributes to the female predominance of IBS. Aim: Identify the impact of the estrous cycle on nociceptive signaling and compare the effects of fecal supernatants (FS) from male and female IBS patients on abdominal pain pathways. Methods: Current clamp recordings measured rheobase and voltage clamp measured voltage-gated Na+ current in thoracolumbar dorsal root ganglia (DRG) neurons. FS from male and female IBS patients reporting high levels of abdominal pain were used. FS were perfused through male, female, and ovariectomized murine colonic preparations while performing extracellular colonic afferent nerve recordings to measure changes in action potential frequency during spontaneous firing and in response to colonic distension. Phase of estrous cycle in female mice was determined through analysis of vaginal swabs. Ovariectomies were performed 4 weeks prior to assays. Results: Current clamp recordings revealed an increase in excitability due to a 20% reduction in rheobase in DRG neurons taken from proestrus/estrus female mice compared to males, metestrus/diestrus females and ovariectomized females (p < 0.05). Voltage-gated Na+ current density was increased by 40% in neurons from proestrus/estrus mice compared to metestrus/diestrus female and male mice (p < 0.01). Extracellular afferent nerve recordings revealed that FS from female IBS patients reporting high abdominal pain (N=3) increased afferent nerve discharge (p < 0.05) in proestrus/estrus female mice by 70%. Single unit analysis of nociceptive axons showed that their activation was increased over 50% following FS perfusion. H owever, this excitatory effect was abolished in ovariectomized mice. Interestingly, FS from male IBS patients reporting high abdominal pain (N=4) had no effect in male mice while female IBS patient FS (N = 6) increased afferent nerve discharge (p< 0.05). Conclusion: This work suggests that the estrous cycle impacts abdominal pain signaling, which may contribute to the female predominance of IBS. This work is funded by CIHR and The Weston Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Associations Between Grip Strength and Cerebral Hemodynamics in Young and Middle-Aged Adults
Authors: Rosonke Rachel , Frescoln Abby , Reed Krista , Gidley John , Churchill Sydney , Meyer Jacob , Lefferts Wesley 
Published: May 2024

Aerobic fitness and aerobic exercise are widely accepted as having protective effects on cognitive function and brain health, with less understood regarding muscular fitness and resistance exercise. Strength is beneficially associated with cognitive function, but the mechanisms underlying this relationship remain understudied and may relate to cerebral hemodynamics. The purpose of this study was to examine the associations between strength and cerebrovascular hemodynamics in young and middle-aged men and women. It was hypothesized that greater strength would be associated with better cerebral hemodynamics (greater mean blood velocity, lower pulsatility, greater pulsatile damping). Ninety-two generally healthy adults between 18-64 years old (36±16 yrs; BMI 25.9±4.0 kg/m2; n=39 women) underwent a hand grip strength assessment and resting cerebrovascular measures. Grip strength was measured via dynamometer and recorded as the highest value of 3 attempts. Middle cerebral artery (MCA) mean velocity and pulsatility index (PI) were measured via transcranial Doppler. Pulsatile damping was calculated as the ratio between the common carotid artery and MCA PI. Mean arterial pressure was assessed via an oscillometric blood pressure cuff. No significant associations were observed between relative grip strength and MCA mean velocity (r=-0.15), MCA PI (r=0.05), or MAP (r=0.07) after adjusting for age. Greater relative grip strength, however, was associated with greater pulsatile damping after adjusting for age (r=0.21; p<0.05). This relationship appeared to be driven by weak associations within each sex (men, r=0.10; women, r=0.02) that were not statistically significant on their own. Our preliminary results suggest there are no strong relations between grip strength and cerebral hemodynamics among generally healthy young and middle-aged adults after accounting for the effects of age and sex. Future studies should examine sex-specific associations with a larger sample, consider disease states related to cerebrovascular health, and include more comprehensive assessments of muscular strength and performance (e.g., power). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sexual dimorphism in renal metabolism, hemodynamics and diseases
Authors: Xiong Lingyun (Ivy) , Garfinkel Alan , Deeds Eric J. 
Published: May 2024

Age-related decline of renal function is faster in males than in age-matched females, manifesting in increased susceptibility to both chronic and acute kidney diseases among males. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments, where most reabsorption of water and salt happens, with a high energetic demand. Recent work suggests that male PTs undergo excessive oxidative stress to meet the high energetic demand, while female PTs exhibit an anti-oxidation state. However, it remains elusive how the observed molecular differences relate to sex disparities in renal physiology and pathophysiology. Glomerular filtration rate (GFR) is tightly regulated by tubuloglomerular feedback (TGF) within renal tubules to optimize ultrafiltration of plasma and reabsorption of essential molecules. Importantly, GFR shows a sustained oscillatory pattern over time in rodents, and loss of GFR oscillations is associated with cessation of reabsorption activities and with the occurrence of ischemia-reperfusion injuries in the kidney, as well as with systemic hypertension. To study the relationship between intracellular metabolic events and renal physiology, we developed a mathematical model of TGF linking metabolic regulation within PT cells to fluid handling and salt reabsorption in the nephron, using renal blood flow and intra-vital imaging data. Analysis of this model revealed that dynamical properties of the system differ between male and female kidneys, resulting in male kidneys being more prone to stress-induced damage, thus building towards an explanation for sexual dimorphism in renal aging and diseases. With this mechanistic model, our work also provides insight into how pharmacological interventions can be employed to confer renoprotection. The authors received no funding for this study. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Alterations in sphingolipid synthesis during training, detraining, and retraining may alter myogenesis in skeletal muscle
Authors: Weidenhamer Clay , Syed Adam , Huang Yi-Heng , Hernancez-Saavedra Diego 
Published: May 2024

The benefits of exercise on metabolic health and its effectiveness at reducing morbidity risk are well established. Exercise training enhances skeletal muscle metabolism and function, but whether such adaptations persist through detraining and how they are potentiated with retraining are not well understood. Recent evidence has highlighted the role sphingolipids play on skeletal muscle size and function, but how exercise affects sphingolipid metabolism is not yet known. We hypothesize that alterations in skeletal muscle sphingolipid metabolism with exercise training are necessary to enhance muscle mass with further exercise retraining. Here, mice were SEDentary (SED; static cages) or exercise-TRAINed (TRAIN; voluntary wheel running) and chow-fed. We performed body composition analysis (using EchoMRI) and skeletal muscle collection [tibialis anterior ( TA), extensor digitorum longus ( EDL), gastrocnemius ( Gas), Soleus ( Sol), plantaris ( Plant), and levator ani ( LA)] following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Sphingolipid and myogenic gene expression was measured in TA muscle by qPCR. Exercise training concomitantly increased lean and decreased fat percentage ( p<0.05), while increasing Sol muscle mass in TRAIN mice ( p<0.05), compared to SED. This was accompanied by higher sphingolipid metabolism ( Acer1, p<0.05; and Cers1, p=0.058) and myogenic gene expression ( MyoD, Myf5; p<0.05). Following detraining, TRAIN mice had an overall increase in lean-to-fat mass ( p<0.05) while maintaining all individual muscle masses ( p<0.05), compared to SED. This was accompanied by a reduction in gene expression of the sphingolipid receptor S1pr1 and myogenic factor Myf5 ( p<0.05), but no differences in sphingolipid metabolism ( Acer1, Cers1). Lastly, retraining increased lean and decreased fat percentage ( p<0.05) and enhanced the masses of TA, Gas, Sol, and Plant muscles in TRAIN mice ( p<0.05), compared to SED. This was accompanied by a reduced expression of rate limiting sphingolipid synthesis genes Sptlc1 and Sptlc2 and the kinase Sphk1 ( p<0.05), but no differences in Cers1 or myogenic gene expression in TRAIN mice, compared to SED. Overall, our data shows that exercise training and retraining potentiate muscle mass accretion and dynamically regulates sphingolipid metabolism adaptations. These data suggest a potential role for sphingolipids to modulate long-lasting improvements to skeletal muscle. Funding was provided by the University of Illinois Urbana-Champaign. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Understanding the Role of Central Parasympathetic Activation in Opioid-Induced Respiratory Depression and Peripheral Airway Constriction
Authors: Burgraff Nicholas , Moreira Thiago , Baertsch Nathan , Ramirez Jan Marino 
Published: May 2024

Opioid-induced respiratory depression (OIRD) is a primary cause of mortality resulting from opioid overdose. Numerous mechanisms have been identified as contributors to OIRD, such as the suppression of central respiratory rhythmogenesis. Our recent research revealed that opioids' ability to suppress breathing extends beyond the central suppression of rhythmic activity, notably leading to airway constriction, which can culminate in complete obstruction. The autonomic nervous system plays a pivotal role in regulating the tone of airway smooth muscles with the parasympathetic system being mainly responsible for bronchoconstriction, and the sympathetic system facilitating bronchodilation. In this study, we evaluated the hypothesis that exposure to fentanyl results in the disinhibition of parasympathetic motor output, leading to centrally mediated peripheral airway constriction. After administering fentanyl (500μg/kg i.p.), minute ventilation dropped by nearly 50%, primarily due to a decrease in breathing frequency. Transient airflow obstructions during the inspiratory phase were observed following fentanyl administration, as indicated by an increased latency between diaphragm contraction and the start of inspiratory flow. These airflow obstructions were fully reversed by the sympathomimetics salbutamol or epinephrine. To determine whether the transient obstructions were a result of vagal activation, another group of mice underwent vagotomy prior to fentanyl administration. The vagotomy effectively eliminated the occurrence of airflow obstructions following fentanyl administration. Additionally, using neuronal activity-based fos-dependent labeling and in-vitro patch-clamp recordings, we showed that fentanyl administration led to a pronounced activation of parasympathetic motor neurons within brainstem areas, including the dorsal motor nucleus of the vagus and the nucleus ambiguus. Collectively, our findings suggest that fentanyl induces transient obstructions to airflow that may be attributed to heightened central parasympathetic activity, which in turn drives peripheral airway constriction. P01 HL090554 (J.M.R.), R01 HL126523 (J.M.R.), R01 HL144801 (J.M.R.), R01 HL151389 (J.M.R.), F32 HL154558 (N.J.B.), R00HL145004 (N.A.B.) and R01HL166317 (N.A.B.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Short-term treatment of Tat-Beclin1 and endurance exercise enhances autophagy and increases grip strength in old male mice but not in female
Authors: Ghiarone Thaysa , Davis Carina , Rahman Shakibur , Murphy Madelyn , Brahmbhatt Dhruti , Silva Kleiton 
Published: May 2024

Sarcopenia is a geriatric disease causing loss of muscle mass and function, ultimately declining quality of life and causing death. Despite substantial efforts to prevent sarcopenia, there are no approved drugs for treating this muscle disease. Autophagy, a critical process for maintaining muscle health, offers potential avenues for intervention. However, an integrative therapy comprised of an autophagic-specific compound and endurance exercise in old animals has yet to be tested. We hypothesize that combining Tat-Beclin1 (a potent autophagy-specific inducer) and endurance exercise improves muscle force and autophagy in both male and female old mice. Female and male mice at 23 months of age were divided into four groups: Control, Tat-Beclin1 (TB), endurance exercise (Exe), and TB+Exe. Short-term combined treatment underwent for one month. Exercise training at moderate intensity (70% of running peak test) was performed on Mondays, Wednesdays, and Fridays. Tat-Beclin1 administration (15 mg/kg/day) was conducted on Tuesdays and Thursdays. We assessed muscle function through forelimb grip strength and muscle autophagic markers by western blotting. There was no difference in grip strength in female groups. In contrast, there was an increase in grip strength in treated male mice (p<0.05; TB, Exe, and TB+Exe vs. Control group). Notably, the combination treatment in the TB+Exe group outperformed the individual treatments (TB and Exe groups) in enhancing grip strength (p=0.05). Beclin1 and GLIPR2 (a novel autophagic suppressor) were unchanged in both male and female mice. Sequestosome/p62 was decreased in males only, indicating autophagy cargo degradation. Our findings demonstrate that a short-term treatment of Tat-Beclin1 combined with endurance exercise improves grip strength (muscle force) and autophagy in old male mice. Notably, female mice did not exhibit a similar response to the short-term treatment, suggesting that a more extended therapy duration may be necessary to explore potential benefits for female mice. This synergy of an autophagic-specific agonist with endurance exercise may represent a novel strategy to tackle sarcopenia. Camden Health Research Initiative - Startup fundings. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Intersection of chronic contractile activity and lysosomal defects in mediating lysosomal adaptations in skeletal muscle cells
Authors: Moradi Neushaw , Hood David A. 
Published: May 2024

Mitophagy is the cellular process that serves to degrade mitochondria when these organelles lose their potential for ATP production, generate excessive reactive oxygen species, and exhibit a reduced membrane potential. The terminal step of mitophagy is mediated by the lysosome, the organelle that degrades defective cellular cargos. Electron microscopy evidence shows that lysosomes become defective in aging muscle, as well as in lysosomal storage diseases, ultimately leading to cellular pathology. Recent research has shown that chronic contractile activity can induce rapid increases in lysosomal gene and protein expression in muscle. Our objective is to investigate whether this adaptation leads to greater lysosomal content and function, thus enhancing the capacity to degrade defective mitochondria. This result would suggest that reduced lysosomal function in muscle could be rescued by exercise. However, the underlying mechanisms mediating lysosomal turnover and function are not clear. To study this, we simulated lysosomal dysfunction in C2C12 myotubes using short-interfering RNA targeting the lysosomal calcium channel mucolipin-1 (MCOLN1) or the autophagosome-lysosome fusion protein, lysosomal-associated membrane protein 2 (LAMP2). We achieved a 60-70% knockdown, as well as a 40-50% knockdown, after a 24-hour transfection, in each lysosomal marker, respectively. The cells were then subjected to four days of electrical stimulation-induced chronic contractile activity. Changes in gene expression were measured via qPCR, while protein content was measured via western blotting techniques, in addition to lysosomal content and functional assessments via confocal microscopy and flow cytometry. Silencing of MCOLN1 or LAMP2 both resulted in a compensatory increase in the transcript and protein levels of lysosomal genes, including the lysosomal transcription factors TFEB, TFE3, as well as lysosomal cathepsins B and D. Interestingly, contractile activity superimposed on the MCOLN1 or LAMP2 knockdown did not further enhance these compensatory increases. This suggests that contractile activity and the cellular signaling that arises from lysosomal defects, operate similarly to initiate the biogenesis of lysosomes as a negative feedback mechanism to enhance lysosomal degradation capacity. The nature of these signaling pathways, potentially involving changes in lysosome-derived intracellular calcium driving organelle synthesis, recycling, or degradation represent novel avenues for upcoming research investigating skeletal muscle phenotypic adaptations. This work is supported by NSERC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.