bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Age on Maximal Heart Rate in Spinal Cord Injury
Authors: Hamner J. , Picard Glen , Taylor J. Andrew 
Published: May 2023

Objective: To determine whether there is a generalizable relationship between maximal heart rate (HR), age, and injury level in individuals with spinal cord injury (SCI). Methods: Retrospective analysis of aerobic capacity testing (VO2max) of 80 individuals with SCI. Hybrid (arms and legs) functional electrical stimulation (FES) rowing was used as the exercise modality, and multiple objective criteria of a maximal effort had to be achieved so that peak HRs approximated maximal in this population. The relationship between age, maximal HR, and injury level was examined with regression and analysis of covariance, with injury level as a continuous and categorical variable (thoracic vs. cervical). Results: The traditional age-related decline in maximal heart rate is largely preserved (Regression: Maximal HR = 204 – Age, r = -0.63, p < 0.001) in persons with thoracic (n = 42), but not cervical (n = 38), level SCI. There was no effect of sex, motor completeness, or aerobic capacity on this relation in those with thoracic SCI. Individuals with a cervical SCI have a reduced maximal heart rate (136 ± 18 bpm) and does not change with age (p = 0.23). Maximal heart in cervical SCI was not predictable from factors such as age, time since injury, weight, and injury level. Conclusion: Age-predicted maximal heart rate may be suitable for exercise testing and prescription for those with thoracic injuries but should not be used in the cervical spinal cord injured population. This work was supported by NIH grants R01 HL117037 R21 HD088891 and ACL NIDILRR grant 90SI5021. This is the full abstract presented at the American Physiology Summit 2023 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.
Lack of concordance between estimates of sympathetic transduction in humans
Authors: Taylor J , Hamner Jason , Draghici Adina 
Published: May 2023

The transduction of sympathetic nervous outflow into arterial vasoconstriction is critical for blood pressure homeostasis. Hence, there is an emerging field of sympathetic transduction to study human health and disease. Much of this work examines sympathetic transduction in response to spontaneous bursts of sympathetic activity. For these analyses, the dependent variable can be beat-by-beat changes in either systemic pressure (‘neurohemodynamic)’ or regional vascular conductance (‘neurovascular’). However, few studies have explored the concordance between changes in these two relations within individuals. Hypoxia induces increased sympathetic activity that is not accompanied by increased blood pressure; therefore, sympathetic transduction would seem to be altered. We assessed both ‘neurohemodynamic’ and ‘neurovascular’ sympathetic transduction during normoxia and sustained hypoxia (~80% SpO2) in young healthy individuals (N=7). Because hypoxia also induces tachycardia and tachypnea, we also assessed transduction(s) as a function of time rather than beat and after filtering out respiratory effects. Hypoxia induced significant (p<0.10) changes in heart rate (60+/-2 vs. 78+/-4 beats/min), respiration (5.8+/-0.3 vs. 8.7+/-1.2 L/min), and sympathetic activity (1431+/-256 vs.2066+/-470 aiu/min), but not in diastolic blood pressure (73+/-2 vs. 76+/-2 mmHg) or leg blood flow (11+/-1 vs. 11+/-1 cm/sec). This resulted in greater ‘neurohemodynamic’ (p<0.01) but no change in ‘neurovascular’ (p=0.94) sympathetic transduction. However, transduction(s) assessed as a function of time and after respiratory filtering demonstrated no effect on ‘neurohemodynamic’ (p=0.24) with a reduced ‘neurovascular’ (p=0.10) sympathetic transduction. These findings indicate that beat-by-beat systemic and regional estimates for transduction from spontaneous bursts of sympathetic activity may not reflect the linear relationship between sympathetic nervous outflow transduced into arterial vasoconstriction for blood pressure homeostasis. In addition, physiologic confounders, such as changes or differences in chronotropic and/or ventilatory state can exert profound influences on the estimated sympathetic transduction(s) and so should be considered if these analyses are to be pursued. This is the full abstract presented at the American Physiology Summit 2023 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 acute removal of metformin induces mitochondrial remodeling and increases mitochondrial respiration
Authors: Bubak Matthew , Davidyan Arik , O'Reilly Colleen , Doidge Stephen , Britton Steven , Koch Lauren , Miller Benjamin 
Published: May 2023

Metformin is a candidate to slow biological aging and extend healthspan, as it reduces the risk of morbidity and mortality in people with type 2 diabetes. However, it is not clear how metformin impacts individuals absent of chronic disease. This unknown is important to answer before prescribing metformin to healthy individuals to prolong the healthspan. It has been shown that metformin creates an inefficiency in energy transfer by accumulating within the mitochondria. Therefore, we hypothesized that the effects of metformin on healthspan are context specific; beneficial in the context of low energy demand/mitochondrial capacity but detrimental in the context of high energy demand/mitochondrial capacity. To test this hypothesis, we used 18-month, male rats selectively bred for low and high treadmill running capacity (LCR/HCR) as models of low and high intrinsic mitochondrial function. For both HCR and LCR, we used high-resolution respirometry (Oroboros O2K) on skeletal muscles from controls (CON), 4 weeks of metformin-treatment (MET), 4 weeks of metformin-treatment with a 48-hour metformin washout (MET-WO), and 48-hour washout with metformin added back to the respirometry chamber (MET-WO-SPIKE). A week prior to sacrifice, we labeled the rats with deuterium oxide to assess protein turnover as an indicator of mitochondrial remodeling. In gastrocnemius muscle, the HCR MET-WO had greater Complex I (CI), CI+Complex II (CII), and maximal respiration (MaxR) (115 ± 23, 164 ± 38, 157 ± 35 pmol/(s✕mg), respectively) compared to the CON (70 ± 24, p = 0.02, 114 ± 32, p = 0.01, 115 ± 40 pmol/(s✕mg), p = 0.04, respectively), and MET (63 ± 54, p = 0.007, 90 ± 50, p < 0.001, 91 ± 48 pmol/(s✕mg), p = 0.002, respectively). The HCR MET-SPIKE group had greater CII (83 ± 33 pmol/(s✕mg)) and MaxR (86 ± 35 pmol/(s✕mg)) compared to the MET (p = 0.007 and p = 0.002, respectively). In the soleus, MET-WO (4.15 ± 0.33%/day) had greater mitochondrial fractional synthesis rates (FSRs) compared to MET (3.12 ± 0.62%/day, p = 0.001) in the HCRs. In the LCRs, MET-WO (4.61 ± 0.42%/day) had greater FSRs compared to CON (p < 0.001, 3.07 ± 0.67%/day) and MET (3.12 ± 0.61%/day, p = 0.001). In the tibialis anterior, MET-WO (3.47 ± 0.80%/day) had greater FSRs compared to the MET (2.41 ± 0.47%/day, p = 0.04) within the HCRs with no differences in the LCR. These data show that metformin reduces mitochondrial respiration in HCR rats but not in LCR rats. The presence of metformin produced a greater subsequent response in HCR compared to LCR as shown by its acute removal revealing metformin-induced mitochondrial remodeling. This is the full abstract presented at the American Physiology Summit 2023 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.
Heart rate fragmentation in renovascular hypertensive rats
Authors: Silva Thais , Buzinari Tereza , Silva Carlos , Castania Jaci , Salgado Helio , Silva Luiz , Fazan Jr Rubens 
Published: May 2023

Although rapid oscillations of the heart rate (HR) are attributed to vagal modulation of the heart, a pattern of ultra-rapid HR variation has been named heart rate fragmentation (HRF). It is a recently proposed approach to evaluate sino-atrial instability characterized by the presence of numerous inflections points in a series of successive values of cardiac intervals. HRF is increased in aging and coronary diseases. Hypertension markedly alters HRV indices and might affect HRF as well. This study aimed to investigate the HRF in renovascular hypertension in rats. Wistar rats were anesthetized, and hypertension was surgically induced by partial constriction of the left renal artery with a silver clip with a 0.2 mm gap. In one kidney one clip (1K1C) hypertension model, the contralateral kidney was removed. In two kidneys one clip (2K1C) model, the contralateral kidney was kept intact. Sham-operated control rats underwent to same surgical procedures without receiving the clip around the renal artery. After 45 days (2K1C) or 60 days (1K1C), animals were instrumented with a catheter into the femoral artery, and on the following day, their arterial pressure (AP) was directly recorded without the effect of anesthesia. For HRF analysis, pulse interval (PI) series were generated and transformed into a sequence of symbols “-1,” “0,” or “1” when the difference between successive PI values (transitions) was negative, zero, or positive, respectively. Following, sequences of 4 consecutive symbols were classified according to the number of transitions. The total percentage of inflection points (PIP) and the percentage of sequences with zero (W0), one (W1), two (W2), or three (W3) inflection points were quantified. As expected, the arterial pressure increased in both groups of hypertension rats compared to control counterparts. All HRF indices were found similar in 1K1C hypertensive rats compared to their control counterparts. Nevertheless, in 2K1C hypertensive rats HRF was found to be lower than normotensive controls (PIP: 64±7 vs. 79±1% and W2: 30±1 vs. 39±1% in 2K1C and normotensive controls, respectively). In conclusion, high blood pressure itself does not affect HRF, although, depending on the model of hypertension used, HRF can be markedly impaired. The interpretation of these findings is challenging, and the high levels of angiotensin in the 2K1C model may affect cardiac pacemaker cells, making their action potentials more stable than unstable. However, the specific mechanisms by which this could happen still need to be studied. Funding Sources: FAPESP, CAPES and CNPq This is the full abstract presented at the American Physiology Summit 2023 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 effects of beta-hydroxybutyrate on mitigating uric acid-induced changes in muscle cell mitochondrial bioenergetics
Authors: Larson John , Remund Nicole , Saito Erin , Warren Cali , Bikman Benjamin 
Published: May 2023

Uric acid accumulates in the body in disease states and aggravates myriad pathologies, including joint pain, insulin resistance, and more. The mediating mechanisms of uric acid-induced disruption is via alterations in inflammatory status and direct effects on mitochondrial function, including disrupted respiration. Interestingly, the ketone beta-hydroxybutyrate (bHB) tends to have the opposite effects. In part, the relevance for this project is borne from the available evidence that indicates ketogenic diets tend to increase uric acid, while paradoxically improving metabolic outcomes, including mitochondrial function. Accordingly, the purpose of this work was to evaluate the competing effects of uric acid (UA) and bHB on mitochondrial bioenergetics in muscle cells. C2C12 muscle cells treated with UA (500 μM) tended to manifest reduced mitochondrial respiration across all conditions, particularly in a basal state (glutamate+malate), compared with control. In contrast, bHB (5mM) maintained respiration at normal levels throughout. The combination of bHB with UA increased respiration levels above UA alone, suggesting a protective effect. Future analyses will further phenotype the effects of these treatments on the production of reactive oxygen species and activation of inflammatory pathways. This is the full abstract presented at the American Physiology Summit 2023 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.
Hybrid Rat Diversity Program (HRDP): A renewable rat resource for systems genetics
Authors: Dwinell Melinda , Takizawa Akiko , Malloy Lynn , Tutaj Monika , Schilling Rebecca , Geurts Aron , Kwitek Anne 
Published: May 2023

Rats are a major model for studying complex disease mechanisms, behavioral phenotypes, environmental factors, and for drug development and discovery. Inbred rat strains control for genetic background and allow for repeated, reproducible molecular, cellular, and whole animal phenotyping. Genetic susceptibility to disease, sensitivity to environmental elements, and pharmacogenomics are critical components of the concepts of precision medicine. The Hybrid Rat Diversity Program (HRDP) is a renewable rat resource that combines the power of genetic stability through inbred strains, power for genomic mapping strategies through genetic diversity and recombinant inbred strains, and strength in an animal model that mirrors many human disease traits. The HRDP was designed to include 96 inbred rat strains with genomic and physiological diversity to maximize power to detect specific genetic loci associated with complex traits while maximizing the genetic diversity among strains. The 96-strain panel consists of 33 genetically diverse inbred strains and two panels of recombinant inbred panels: FEXL/LEXF (33 strains, Japan) and HXB/BXH (30 strains, Czech Republic). Currently, 85% of the classic inbred and 68% of the RI strains are available for experiments. Whole genome sequencing of 89 unique strains have been sequenced. Strain specific variants are available at the Rat Genome Database through the HRPD Portal, the strain pages, and genomic tools. RNA sequencing of kidney, thymus, and muscle for the classic inbred strains are underway. The HRDP will provide a genetically stable population of rat strains with fully sequenced genomes, transcriptomes for brain and liver, and general phenotypic characterization to be used for systems genetic studies and fine mapping of complex traits. National Institutes of Health, Office of the Director, R24OD024617 This is the full abstract presented at the American Physiology Summit 2023 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.
Microglia Senescence Mediates Inflammation in the Hypothalamus of High-Fat Diet Induced Obese Mice
Authors: Plakkot Bhuvana , Di Agostino Ashley , Balasubramanian Priya , Subramanian Madhan 
Published: May 2023

Hypothalamus is a major regulatory center in the brain responsible for various homeostasis processes. Distinct neurons and glial cells, including microglia support the cardiovascular functions in the hypothalamus. An important cardiovascular regulatory nucleus in the hypothalamus is the Paraventricular Nucleus (PVN). Previous studies from our laboratory showed evidence for cellular senescence in the PVN. Senescence is a state of irreversible growth arrest in proliferating cells, which has been implicated in several neurodegenerative diseases. Microglia, is the resident macrophage cells of the brain that can phagocytose and initiate local inflammatory responses. Upon chronic inflammatory signaling, microglia lose its phagocytic property and enters a state of activation and proliferation. We analyzed hypothalamus from young adult mice fed with either chow (6 kcal% fat) or High Fat Diet (HFD; 60 kcal% fat) for a period of 16 weeks. Cell sorting of activated microglia using a benchtop microfluidic cell sorter revealed an increase in activated microglia in the hypothalamus after chronic HFD feeding. Microglial activation has been associated with promotion of a senescence phenotype and induction of inflammation through senescence associated secretory phenotype (SASP). To investigate this, we analyzed senescence markers in the hypothalamus. Real-time PCR revealed elevated senescent markers p53, p21 and p16, along with a significant increase (P<0.05) in SASP factors such as IL1β, MCP1 and TNFα in the HFD group compared to controls. Immunofluorescence studies confirmed the presence of senescent Iba1+ microglial cells in the PVN of HFD mice compared to their chow counterparts. Taken together, these findings suggest that senescent microglia could play a central role in the hypothalamic inflammation in HFD-induced obesity and targeting microglia will help in developing novel preventive and treatment strategy for obesity associated cardiovascular diseases. National Heart, Blood and Lung Institute grant R15HL148844; American Heart Association Institutional Research Enhancement Award – 959725. This is the full abstract presented at the American Physiology Summit 2023 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.
Neuromuscular coupling of obligatory respiratory muscles to inspiratory pressure is reduced in dystrophic (mdx) mice
Authors: Maxwell Michael , O' Halloran Ken 
Published: May 2023

Neuromuscular coupling (NMC) is a recognised clinical index of inspiratory muscle function which reflects the efficiency of conversion of neural activation to inspiratory pressure. Duchenne muscular dystrophy (DMD) is characterised by respiratory insufficiency culminating in respiratory failure. We investigated inspiratory pressure generating capacity and electrical activation of obligatory inspiratory muscles in X-linked muscular dystrophy ( mdx) mice, to evaluate NMC of diaphragm, external intercostal and parasternal intercostal to inspiratory pressure across a range of behaviours in early established to late progressive disease.In urethane anaesthetised mice (1.7 g/kg i.p.), inspiratory pressure was recorded via a pressure transducer positioned in the thoracic oesophagus. Diaphragm EMG activity was recorded using needle electrodes. Studies were performed in male wildtype (WT) and mdx mice at 4, 8, 12 and 16 months old. Recordings were made at baseline and during sustained tracheal occlusion to task failure, defined as an inability to sustain peak pressure. Peak pressure was determined from the average of five successive peak efforts at the maximum response. The corresponding peak inspiratory EMG activities were determined. Two factor (age x genotype) analysis of variance was performed.Obligatory muscle EMG activities were significantly lower in mdx mice from 4 months of age. Peak inspiratory pressure was significantly greater in mdx at 4 months of age. At 8 months, peak inspiratory pressure was equivalent between WT and mdx followed by a significant decrease in peak inspiratory pressure in 12- and 16-month-old mdx. NMC was lower in mdx mice across the ventilatory and non-ventilatory range, emerging early in dystrophic disease.Reduced NMC of obligatory muscles to inspiratory pressure in mdx mice reveals a greater reliance on accessory muscles to support respiratory performance in dystrophic disease. Remarkably, this burden is adequately accommodated in early disease with a preserved capacity to generate peak inspiratory pressure. We reason that the loss of compensation afforded by accessory muscles to peak inspiratory pressure generation underpins the emergence of respiratory compromise in advanced disease. Our results may have implications for the understanding and treatment of DMD. Funded by Science Foundation Ireland SFI/19/6628 INSPIRE DMD. This is the full abstract presented at the American Physiology Summit 2023 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.
Developmental expression of mechano-stimulated Ca2+ transport pathways in kidney organoid tubules
Authors: Carrisoza-Gaytan Rolando , Gupta Navin , Hiratsuka Ken , Kroll Katharina , Morizane Ryuji , Lewis Jennifer , Satlin Lisa 
Published: May 2023

Kidney organoids derived from human pluripotent stem cells exhibit glomerular- and tubular-like structures. As the technology for culturing organoids advances, the goal of promoting terminal differentiation demands that priority be given to characterization of their physiological function. To begin to functionally phenotype organoids, we examined mechano-induced changes in intracellular Ca2+ concentration ([Ca2+]i) and signaling pathways in tubules isolated from maturing organoids. We found that tubules microdissected from organoids cultured under static conditions and exposed to basolateral Yoda1 (5 μM), an activator of the mechanosensitive Ca2+ permeable channel Piezo1, exhibited an increase in [Ca2+]i of increasing magnitude with advancing days in culture (Carrisoza-Gaytan et al., ASN, 2021). This observation suggests that organoids undergo a developmental increase in the abundance and/or activity of Piezo1 and /or maturation of signal transduction pathways mediating this response with advancing days (d) in culture.To begin to examine these possibilities, transcript expression levels of the putative mechanosensor PIEZO1 and Ca2+ transport proteins TRPV4 and PMCA1 (plasma membrane Ca2+ ATPase) were measured in organoids (n=3-6) cultured for 8, 21, 35 and 49 d by RT-qPCR. ACTB (encoding β-actin) and GAPDH transcript expression were included as housekeeping genes. Abundance of Piezo1 and TRPV4 channel protein expression was studied by immunofluorescence (IF) and confocal microscopy in organoids (n=3) at 21 and 49 d in culture.RT-qPCR demonstrated an increase in PIEZO1 (28.1±2.0 fold, p≤ 0.05), TRPV4 (5.3±0.8 fold, p≤ 0.01) and PMCA1 (1.8±0.1 fold, p≤ 0.05) between 8 and 49 d in culture when normalized to GAPDH expression; we found that ACTB expression also increased with organoid maturation (1.9±0.1 fold, p≤ 0.01) when normalized to GAPDH expression during this interval. IF labeling of organoid cryosections revealed an increase in apical Piezo1 (3.2±0.6 fold, p≤ 0.001) and TRPV4 (1.5±0.1 fold, p≤ 0.05) in tubular structures at 49 vs 21 d in culture.These results demonstrate a developmental increase in molecular expression and cell localization of Ca2+ transport proteins responsible for the transduction of external mechanical stimuli into intracellular Ca2+ signals in organoids cultured over time. UC2DK126023 (JAL, LS, RM); DP2 DK133821 (RM); R01 DK038470 (LMS); R01 DK129285 (LMS); P30 DK079307 (LMS) This is the full abstract presented at the American Physiology Summit 2023 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.