bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implications of alcohol use for aging-associated skeletal muscle dysfunction
Authors: Simon Liz , Bourgeois Brianna , Welsh David , Molina Patricia , Rodriguez-Graciani Keishla 
Published: May 2024

Background: Alcohol use decreases skeletal muscle (SKM) strength and function. Alcohol use is disproportionately on the rise among older individuals, with 25% engaging in heavy drinking and 11% reporting binge drinking. The significant increase in life expectancy in the United States leads us to predict that alcohol use will be an important factor exacerbating SKM function in chronological aging, increasing the risk of poor physical performance and frailty. The objective of the study was to assess the impact of recent alcohol use on measures of physical performance and on muscle differentiation and bioenergetic capacity among people over the age of 60. Methods: We conducted a prospective cross-sectional study. Sedentary people over the age of 60 years were recruited from the Greater New Orleans Area. Participants were assessed for physical performance and vastus lateralis muscle biopsies taken for biochemical analysis. Recent alcohol misuse was defined as phosphatidyl ethanol (PEth), a biomarker of alcohol use, levels >20 ng/ml. Results: Preliminary analysis of data from 13 participants (PEth> 20 ng/ml, n=5) showed no differences in hand grip strength (Means± SD-31.08±9.8 and 33.17±8.4 kg respectively), 30-sec sit to stand test (10.5± 1.8 and 10.6± 3.9 number respectively), and Timed up and go Test (13.5± 2.6 and 11.4± 3.1 seconds respectively) among participants with PEth < 20 ng/ml compared to those with PEth >20ng/ml. Data collected from myotubes derived from myoblasts isolated from SKM biopsies from participants with PEth >20 ng/ml showed increased proton leak (indicator of poor mitochondrial bioenergetic health) and lower myotube density (p=0.06, Cohen’s d = 1.9) compared to myotubes from participants with PEth <20 ng/ml. Conclusions: Preliminary analysis indicates that recent alcohol use dysregulates muscle bioenergetic and differentiation capacity that are not associated with significant differences in physical performance tests. Ongoing analysis will identify confounding factors, and whether cumulative lifetime alcohol use contributes more significantly to physical performance and frailty measures among older people. R21AA030869, Pilot funding Department of Physiology LSUHSC-NO, P60AA009803. 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.
An Acute Bout of Subconcussive Head Impacts Does Not Change Intracranial Pressure
Authors: Ryan Caleb , Gorini Pereira Felipe , Olesh Margaret , Mick Lauryn , Kawata Keisuke , Johnson Blair D. 
Published: May 2024

Purpose: Subconcussive head impacts (SHI) are known to cause a variety of negative sequelae including increased plasma concentrations of neuronal structural and glial proteins, attenuated neurovascular coupling, and impaired vestibular function. Traumatic brain injuries are associated with an increase in intracranial pressure (ICP). However, it is unknown whether an acute bout of SHI increases ICP. We tested the hypothesis that estimates of ICP via ultrasound assessments of optic nerve sheath diameter (ONSD) would be greater following a single session of repetitive SHI versus a control condition. Methods: 14 healthy participants (age: 19±2 y; BMI: 21±4 kg/m2, 3 women) with at least 3 y of soccer heading experience completed two experimental conditions in a randomized crossover design. 20 soccer headings were used to induce repetitive SHI and 20 soccer kicks were used as the control condition. A soccer ball was projected from a soccer JUGS machine (40 km/h, 12.2 m away) every 30 s for both conditions. ONSD assessed via ultrasound is associated with direct measures of ICP. Subjects were in the supine position during ONSD (transverse plane, each eye; B-mode linear array ultrasound), heart rate (HR; 3-lead ECG), and mean arterial blood pressure (MAP; photoplethysmography) measurements conducted at baseline prior to heading/kicking and at 2 h, 24 h, and 72 h post. ONSDs were measured 3 mm under the bulb in triplicate for each eye and the mean values were used for analyses. Inter-eye ONSD values were also averaged for analyses. Clinical intervention to alleviate elevated ICP is indicated when ONSD is > 5.0 mm. Data were analyzed using a mixed-effects model with repeated measures with time and condition as within subject factors. Data are presented as mean ± SD if statistically significant. Results: No subjects had an ONSD > 5.0 mm in either eye following heading or kicking. Left ONSD was greater than baseline at 2 h post heading (2.89 ± 0.25 mm vs. 2.99 ± 0.27 mm; p = 0.0157) and greater than baseline at 2 h (2.92 ± 0.37 mm vs. 2.98 ± 0.31 mm; p = 0.0352) and 72 h (3.08 ± 0.26 mm; p = 0.0067) post kicking. Left ONSD at 72 h post kicking was greater than heading (3.08 ± 0.26 mm vs. 2.93 ± 0.25 mm; p = 0.0022). There were no interaction effects for right ONSD (p = 0.4686), average ONSD (p = 0.1178), HR (p = 0.1039) or MAP (p = 0.3889). Conclusion: Neither the heading nor kicking intervention elicited a clinically relevant ONSD that would require medical attention. Contrary to our hypothesis, an acute bout of 20 soccer headers did not evoke greater ONSD in healthy subjects versus kicking. Therefore, our data indicate that a single session of SHI does not increase ICP. 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.
Generation of an Inducible Avp Knockout Mouse Line Using CRISPR/Cas9 and Cre/LoxP
Authors: Khan Shaza , Chen Lihe , Khundmiri Syed , Chou Chung-Lin , Knepper M.A. 
Published: May 2024

Background: Arginine vasopressin (AVP) is a peptide hormone coded by the Avp gene, synthesized in the hypothalamus and secreted by the posterior pituitary. Dysregulation of AVP secretion contributes to a variety of human diseases. Previous studies of functional roles of AVP have been largely dependent on the use of Brattleboro rats, which manifest a spontaneous mutation in the Avp gene and lack circulating AVP. Despite their utility, Brattleboro rats are diffcult to breed owing largely to the fixed nature of the Avp mutation, resulting in increased neonatal death and behavioral effects in the adults. Consequently, commercial breeders have ceased production, despite a continued need. To fill this need, we have now created a mouse model with a tamoxifen-inducible deletion of AVP. Methods: We employed CRISPR/Cas9 to target the desired regions (first intron and 3' downstream) within the Avp gene. Successful insertion of the two loxP sites was confirmed by PCR using primers flanking the targeted regions. Restriction enzymes BamHI or EcoRI were used to confirm correct targeting. For additional confirmation, PCR products were cloned into the TA-cloning vector and sequenced. Mice harboring the floxed allele were mated to B6.Cg-Tg(CAG-cre/Esr1*)5Amc/J mice that globally express a tamoxifen-inducible Cre recombinase. Results: The resultant homozygous conditional knockout mice ( Cre+ Avpflx/ flx) are viable, fertile, and show no signs of polydipsia or polyuria prior to induction, indicating that the conditional alleles retain their wild-type function. Induction of Cre-mediated recombination by administration of tamoxifen (2-3 mg q.d., i.p. for 5 days) in 8-week-old mice resulted in a decrease in urine osmolality from 2076±138 to 122±6 mOsm/kgH2O on day 31 after induction (p<0.0001). Sanger sequencing demonstrated the expected 1245 bp deletion at the Avp locus. The kidney parenchyma was structurally normal with no evidence of medullary atrophy 6 weeks after induction. Immunoblotting of AQP2 in the inner medulla showed a significant decrease in AQP2 band density in Cre+ Avpflx/ flx mice to 27±14 % of values in Cre− floxed control mice (p<0.05). Conclusion: We developed an inducible AVP knockout mouse line ( Cre+ Avpflx/ flx) that will be shared with the research community and are likely to be useful for further study of regulation of water balance and polycystic kidney disease, as well as neural, vascular, and metabolic roles of vasopressin. The work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute. 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.
Ventilatory long-term facilitation following acute intermittent hypoxia in unanesthetized rats: influence of short hypoxic episodes and changes in metabolic rate
Authors: Jones Aaron , Mitchell Gordon 
Published: May 2024

Plasticity is a hallmark feature of the neural system controlling breathing. Acute intermittent hypoxia (AIH) elicits plasticity in multiple respiratory motor pools ( e.g., phrenic, intercostal, XII, etc.) and has emerged as a promising therapeutic approach to restore lost respiratory (and non-respiratory) function in people with spinal cord injury and other clinical disorders that compromise movement. In anesthetized rats during the rest phase, AIH-induced phrenic long-term facilitation is enhanced when the AIH consists of short (1-min) versus longer (5-min) moderate hypoxic episodes (PaO2 ~40-50 mmHg), even with the same cumulative duration of hypoxia (15-min). However, since respiratory plasticity is influenced by a variety of behavioral and physiological factors such as sensory feedback, lung/chest wall mechanics and arousal state, the effectiveness of specific AIH protocols may differ when implemented in unanesthetized rats. Since it is unknown how hypoxic episode duration impacts ventilatory long-term facilitation (vLTF) in unanesthetized rats during the rest phase, we initially tested the hypothesis that short (1-min) hypoxic episodes (FIO2 = 0.09) elicit vLTF in young male Sprague-Dawley rats via whole-body plethysmography; metabolic CO2 production was also assessed. Following 15, 1-min hypoxic episodes, significant vLTF was observed, and this effect was more pronounced when ventilation was normalized to metabolic rate ( i.e. VE/VCO2; p < 0.05). AIH-induced vLTF was accompanied by hypometabolism and a post-hypoxic temperature decrease (p < 0.01), consistent with previous work. Additional studies will be performed to compare these results with “traditional” AIH protocols ( i.e., 5-min hypoxic episodes), and across the rats’ rest versus active phase. In perspective, these results set the stage for future investigations concerning the optimization of AIH protocols in unanesthetized rodent models, including rodent models of injury or disease. NIH HL148030 & 147554 (Mitchell). 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.
C2 Spinal Cord Hemisection Reduces Mitochondrial Volume Density in Phrenic Motor Neurons
Authors: Haggaz Ali , Fogarty Matthew , Mantilla Carlos B. , Sieck Gary C. 
Published: May 2024

The diaphragm muscle (DIAm) is the major inspiratory pump for breathing. Neural control of the DIAm during breathing involves the recruitment of fatigue resistant motor units comprising smaller phrenic motor neurons (PhMNs), which innervate type I and IIa fibers. More fatigable DIAm motor units comprise larger PhMNs that innervate type IIx/IIb fibers, which generate greater forces but are more fatigable. The fatigable motor units are only infrequently recruited for expulsive behaviors of the DIAm. Thus, there are marked differences in the activation history of DIAm motor units. Consistent with their higher activity levels, previous studies from our lab have shown that smaller PhMNs and type I and IIa DIAm fibers have greater mitochondrial volume density (MVD). PhMNs located in the cervical spinal cord (C3-C5) receive direct excitatory input from medullary premotor neurons, which is primarily ipsilateral. Thus, C2 spinal cord hemisection (C2SH) disrupts the neural pathway essential for breathing and significantly reduces DIAm activity on the same side. Therefore, we hypothesized that C2SH significantly reduces MVD of smaller PhMNs. In Sprague Dawley rats, PhMNs on both sides were retrogradely labeled by intrapleural injection of cholera toxin B (CTB) 3 days prior to C2SH (right side). In addition, DIAm EMG activity was recorded on both sides by inserting bipolar electrodes. Mitochondria were labeled by intraspinal injection of MitoTracker Red and imaged in identified PhMNs using 3D confocal microscopy. A series of optical slices (0.5 mm) of PhMNs were deconvolved to improve contrast, then thresholded for MitoTracker labeling followed by 3D reconstruction, providing detailed images of mitochondrial morphometry and distribution within PhMNs. In sham rats, the MVD of smaller (lower somal surface area) PhMNs was higher compared to larger PhMNs. C2SH reduced DIAm EMG activity on the ipsilateral side across a 14-day period, while activity on the contralateral side increased. After 14 days, C2SH reduced MVD by ~25% in smaller PhMNs on the ipsilateral side. We conclude that the reduced activity of smaller PhMNs induced by C2SH induced mitochondrial morphological changes, most likely due to reduced mitochondrial biogenesis. These results indicate that reduced DIAm activity associated with mechanical ventilation may impose mitochondrial remodeling that reduces mitochondrial oxidative capacity in PhMNs. These adaptations may disrupt mitochondrial function and impair weaning from mechanical ventilation. Research support by NIH grants HL166204, HL146114 and AG44615. 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.
Effects of aging and exercise on Mitochondria-ER contacts (MERCs) in skeletal muscle
Authors: Allen Ryan J. , Kronemberger Ana , Pereira Renata O. , Anderson Ethan J. , Shi Qian , Song Long-Sheng , Lira Vitor A. 
Published: May 2024

Mitochondrial dysfunction is a prominent factor contributing to age-associated loss of muscle mass and force (a.k.a., sarcopenia). Yet, events preceding age-related mitochondrial dysfunction, which may allow the development of new therapies, remain poorly understood. Physical coupling of the outer mitochondrial membrane (OMM) to the endoplasmic or sarcoplasmic reticulum (ER), termed mitochondria ER contact sites (MERCs), modulate several mitochondrial processes influencing cellular function. In an energetically demanding and primarily post-mitotic tissue, we hypothesized that alterations in MERCs correlate with the development of sarcopenia. We also hypothesized that MERCs respond to exercise training and may contribute to beneficial muscular remodeling in older adults. To address these, we studied three age groups of male C57BL6N mice: young adults (Y, 5 mo. of age), old (O, 20 mo. of age), and very old (VO, 31 mo. of age). An additional group of old mice underwent 8-9 weeks of treadmill training (OET). Muscle mass and contractile function decreased with aging; VO animals displayed ~25% decline in maximum tetanic force vs. Y mice (p<0.0001). Fatigability (assessed via repetitive sub-maximal contractions) increased by ~10% with aging but was attenuated in the OET group (p<0.001). In saponin-permeabilized muscle fibers, aging did not affect mitochondrial oxidative capacity. However, H2O2 emission was nearly doubled in the O group (p<0.01) and this trend was partially alleviated by exercise training. Assessed via TEM, aging decreased the size of MERCs (i.e., length of SR and OMM apposition) by around 20% (p<0.01). Interestingly, OET animals displayed ~50% increase in MERC coverage (i.e., proportion of OMM covered by SR; p<0.0001). Immunoblots of cellular MERC fractions revealed that MERC proteins associated with calcium exchange were altered with age and exercise. The OMM channel, VDAC1, was reduced by 20% in O muscles (p=0.02), while Grp75, a tether protein, was ~25% higher in OET (p=0.02). Quantitative proteomic analyses revealed various MERC proteins being modified by aging and exercise. Our findings indicate that changes in MERC structure and protein composition may underlie early events preceding the development of sarcopenia and that exercise-mediated adaptations at MERCs may contribute to the beneficial adaptations in aging skeletal muscle. Supported by the University of Iowa Fraternal Order of Eagles Diabetes Research Center (UIowa FOEDRC). 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.
Effects of aging on vasoconstrictor responses of diaphragm arterioles
Authors: Kenney Nathan , Horn Andrew , Schulze Kiana , Weber Ramona , Poole David , Behnke Bradley , Musch Timothy 
Published: May 2024

Introduction: In health, the diaphragm is the most important inspiratory muscle and the only skeletal muscle that is continuously recruited throughout life. Because of the diaphragm’s importance to generating the exercise hyperpnea and wealth of evidence that diaphragm fatigue and exhaustion can impair exercise tolerance, we were interested in whether the exercise intolerance that attends older populations might be associated with altered diaphragm vasomotor control. While it is known that aging compromises peripheral skeletal muscle vasomotor control, it is not known if similar impairments are present in the respiratory muscle vasculature, namely the diaphragm. Therefore, we tested the hypothesis that advanced age decreases diaphragm arteriole contractile responses to alpha-adrenergic agonists. Methods: 4–5 month old Fischer rats and 22–24 month old Fischer rats were divided by age into two groups: young (Y) and old (O). In Y and O, diaphragm first order (1A) arterioles (~200μm diameter, ~2μm in length) were isolated, cannulated, and pressurized to develop spontaneous tone. Following this, contractile responses to cumulative doses of norepinephrine (NE) and phenylephrine (PE) (10−9 to 10−4M) were determined. Results and Conclusion: The physical characteristics of the two groups differed as O were heavier than Y. However, with respect to the diaphragm 1A arterioles, there were no differences in spontaneous tone development (%) or maximal diameter (μm) between Y (38 ± 4%; 132 ± 19μm) and O (37 ± 4%; 157 ± 14 μm; both P >0.05). In diaphragm 1A arterioles, the maximal vasoconstrictor response to NE was also not different between O and Y animals (O: 37 ± 8% vs. Y: 45 ± 1%; p > 0.05). However, the maximal vasoconstrictor response to PE was greater in Y compared to O (O: 29 ± 3% vs. Y: 39 ± 5%; p ≤ 0.05). These data support that aging may reduce a1 adrenergic receptor mediated vascular control, altering the vasoconstrictive responsiveness of diaphragm resistance vessels. We are increasing our group sizes to test the robustness of this conclusion. This work was supported by the Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants awarded to T.I.M and D.C.P. by Kansas State University College of Veterinary Medicine and the National Institute on Aging 1R15AG078060 awarded to B.J.B and D.C.P. A.G.H and K.M.S. were financially supported by Ruth L. Kirschstein National Research Service Awards 1F31HL167618-01 and 1F31HL170643-01, respectively. 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.
Disruption of ER Stress CHOP in beta cells protects from HFpEF pathogenesis
Authors: Srinivas Balaji , Fortuno Paula , Belmadani Souad , Rhaleb Nour-Eddine , Matrougui Khalid 
Published: May 2024

Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) is a multifactorial cardiovascular disorder characterized by diastolic dysfunction, hypertension, and metabolic disturbances. In this study, we aimed to investigate the effect of endoplasmic reticulum (ER) stress C/EBP homologous protein (CHOP) in beta cells on the development of HFpEF. Methods: Eight-week-old male mice, both CHOPflox/flox and CHOPbeta cells −/− were divided into four groups: control ER stress CHOPflox/flox and ER stress CHOPbeta cells −/− mice subjected to standard diet and water. ER stress CHOPflox/flox and ER stress CHOPbeta cells −/− mice fed a high-fat diet (HFD) and L-NAME (0.5 g/L) for five weeks. A comprehensive cardiovascular, metabolic, and histological evaluation was conducted. Results: Following five weeks of HFD and L-NAME, ER stress CHOPflox/flox mice exhibited both clinical and molecular manifestations of HFpEF, encompassing diastolic dysfunction (elevated E/E' ratio), normal cardiac ejection fraction, hypertension, metabolic aberrations, cardiac hypertrophy paired with fibrosis pulmonary (lung) edema, renal injury with fibrotic changes, and reduced exercise tolerance. Vascular endothelial dysfunction was observed. Western blot analysis unveiled a diminished expression of phosphorylated endothelial nitric oxide synthase (p-eNOS) in mesenteric resistance arteries (MRA), concomitant with qRT-PCR data revealing elevated levels of inflammatory markers (Cox2, iNOS, NLRP3) and ER stress markers (CHOP, ATF6, PERK, XBP1, IRE1) in both MRA, heart, and pancreas. Interestingly, ER stress CHOPbeta-cells−/− mice subjected to an HFD and L-NAME were protected from the development of HFpEF and its associated pathologies. These mice displayed improved cardiac and vascular endothelial function, reduced ER stress, and decreased inflammatory factors compared to their ER stress CHOP flox/flox. Conclusion:Our research findings indicate that ER stress CHOP in beta cells plays a pivotal role in the development of HFpEF. Thus, targeting ER stress CHOP in beta cells could be a promising strategy for preventing HFpEF. 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.