bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCPII Inhibition in Macrophages Delays Age-related Muscle Atrophy in Mice
Authors: Su Yu , Tallon Carolyn , Thomas Ajit , Huizar Kaitlyn , Huang Meixiang , Tenora Lukas , Liyanage Wathsala 
Published: May 2024

Age-related loss of muscle mass and strength (Sarcopenia) significantly impairs quality of life in the elderly, yet lacks effective treatments. We previously demonstrated that inhibition of GCPII delayed muscle function decline and neuromuscular junction (NMJ) denervation in an amyotrophic lateral sclerosis (ALS) animal model. As sarcopenia shares NMJ deterioration with ALS, we tested the potent GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) in aging mice, and found that it also preserved muscle function and NMJ integrity. By immunofluorescent staining, we demonstrated that aged mice muscles were associated with GCPII-positive infiltrating macrophages. We next developed a macrophage-targeting GCPII inhibitor delivery system by covalently attaching 2-PMPA to 4th-generation polyamidoamine (G4-PAMAM) dendrimers (D-2-PMPA). The D-2-PMPA was found to inhibit GCPII with IC50= 3.50±0.05 nM. Aged mice muscle showed increased GCPII activity specifically in CD11b+ enriched macrophage cells (138.6±3.0 vs. 336.6±52.9; p<0.05) but not in CD11b− cells. Systemic D-2-PMPA therapy (20 mg/kg 2-PMPA equivalent; IP 3 × /week) completely inhibited the elevated GCPII activity (336.5±52.8 vs. 21.8±9.2 fmol/mg/h; p<0.001). 5-months of D-2-PMPA therapy initiated with 15-month-old mice significantly preserved calf muscle volume (95.0±0.8% vs. 90.4±0.7%; p <0.001), enhanced isometric force (230.2±13.3 vs. 184.0±9.0 mN, female p<0.05; 257.3±21.0 vs. 189.7±19.3 mN, male p<0.05), improved grip strength (96.1±1.6 vs. 90.2±2.2 % of maximum p<0.001) and increased rotarod latency (119.0±6.6 vs. 93.5±9.3 s, female p<0.05; 104.5±5.2 vs. 79.3±4.2 s, male p<0.001). Age-related decline of nerve signal conductivity to muscles was also delayed with D-2-PMPA as observed by improved compound muscle action potential (CMAP) latency (1.28±0.02 vs. 1.38±0.04 ms; p< 0.05) and amplitude (15.2±0.5 vs. 1.27±0.6 mV; p<0.01). Furthermore, NMJ integrity was preserved with treatment as demonstrated by single fiber jitter (5.4±0.3 vs. 7.5±0.5 μs; p<0.01). Overall, our current results support that excessive GCPII activity in muscle macrophages is associated with age-related muscle atrophy, which is improved by GCPII inhibition. This study highlights GCPII inhibition in macrophages as a new therapeutic approach to delay sarcopenia. R01AG078181, R01AG068130, R01NS093416. 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.
Estrogenic re-mapping of the metabolic response to an energy deficit
Authors: Vander Paul , Park Jae , Correa Stephanie 
Published: May 2024

Endothermy is an adaptation that can be traced back hundreds of millions of years and is critical for nearly every aspect of mammalian biology. Despite the advantages associated with a stable internal temperature, endothermy is energetically expensive. To conserve energy when food is scarce, mice have evolved the ability to reversibly enter a regulated state of hypothermia and hypometabolism, known as torpor. We have found that circulating 17β-estradiol, a potent estrogen, inhibits fasting-induced torpor in ovariectomized female mice, yet the signaling mechanisms underlying this estrogenic re-mapping of the metabolic response to an energy deficit remain largely unknown. Recent studies have identified the medial preoptic area of the hypothalamus (MPO) as the central regulator of torpor. MPO neurons that express estrogen receptor alpha have been identified as central coordinators of torpor, and MPO neurons that are activated during torpor broadly express estrogen receptors, suggesting that circulating estrogens may directly modulate torpor-driving neurons in the MPO. To test the hypothesis that circulating estrogens inhibit torpor by acting directly on estrogen-sensitive neurons in the MPO, we delivered 17β-estradiol (E2) directly to the MPO before inducing torpor with a 48-hour fast. Surprisingly, we found that E2 delivered to the MPO was suffcient to inhibit fasting-induced torpor in gonad-intact, but not ovariectomized, female mice. These data demonstrate that E2 signaling in the MPO is insuffcient to inhibit torpor on its own and that there are likely MPO-independent nodes in the body that circulating estrogens act on to inhibit torpor. However, our data also demonstrate that E2 signaling in the MPO does play a role in tuning the torpor response when endogenous gonadal hormones are present, suggesting that the MPO can sense estrogens and engage the appropriate effector circuits to inhibit torpor in certain physiological contexts. Together, these data advance our understanding of how circulating estrogens inhibit torpor in mice — a critical step towards the broader goal of understanding how circulating estrogens influence energy expenditure, and how these pathways can be manipulated to improve metabolic health. NIH RO1 (R01AG066821) - "Estrogenic modulation of neural circuits that control temperature" AHA Predoctoral Fellowship (23PRE1019923) - Estrogenic modulation of hypothalamic neurons that control energy expenditure. 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.
Exercise may be a Novel Strategy to Reduce Vascular Toxicity of Immune Checkpoint Inhibitors in a Mouse Melanoma Model
Authors: Lee Jonghae , Pareek Sumedha , Ballarò Riccardo , Savage Hannah , Patel Hetal , Ko Kyung-Ae , Abe Jun-ichi 
Published: May 2024

Background: Immune checkpoint inhibitors (ICIs) are a cornerstone in advanced melanoma treatment. Unfortunately, ICI-associated cardiovascular toxicity, particularly atherosclerotic events, poses a significant challenge. Identifying interventions to mitigate the cardiovascular toxicity of ICI is critical for enhancing the quality and duration of life in cancer survivors. Given the established benefits of exercise in atherosclerosis prevention, this study explores its potential to reduce ICI-induced vascular toxicity in the context of melanoma. We hypothesized that aerobic exercise would decrease ICI's vascular toxicity in a mouse melanoma model. The primary experimental outcome was endothelial mesenchymal transition (EndMT), an early atherosclerosis indicator. Methods: C57BL/6 mice were subcutaneously injected with 0.8 x 106 BP melanoma cells ( BrafV600E/WT and Pten−/−). Upon tumor palpability, mice were assigned into four groups: IgG, Exercise, anti-PD-1, and anti-PD-1+Exercise. Mice were treated with bi-weekly administration of anti-PD-1 or IgG antibody (150 μg) for three weeks, combined with or without treadmill exercise (12 meters/minute for 45 min per day, five days/week). Body weight was monitored weekly. Following the final treatment, aortic tissues were collected and en face immunofluorescence staining for endothelial marker VE-cadherin (VE-Cad) and vimentin was performed to assess EndMT, then analyzed via confocal microscopy. Results: No significant weight differences were observed between groups. Notably, the EndMT marker vimentin expression was significantly higher in anti-PD-1 treated tumor-bearing mice compared to IgG controls (3.8% vs 0.6%, p=.03) in the atheroprotective laminar flow area. This was reduced by exercise; the anti-PD-1+Exercise group showed significantly reduced endothelial vimentin levels relative to the anti-PD-1 alone (0.8% vs 3.8%, p=.04). Disturbed flow areas did not exhibit notable differences between any group. Conclusions: Aerobic exercise may be protective against vascular toxicity in mice treated with ICIs by promoting atheroprotective flow and potentially inhibiting EndMT. Although these initial results are promising, comprehensive studies are required to ascertain the impact of exercise on preventing ICI-induced EndMT and subsequent atherosclerosis in this mouse melanoma model. Future research will aim to more deeply characterize the process of EndMT following ICI treatment and evaluate the preventive capacity of exercise against atherosclerosis in this context. MD Anderson Cancer Center Melanoma SPORE grant (NCI P50CA221703-05). 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.
Diminished insulin-induced vasodilation of the posterior cerebral artery in db/db mice is associated with reduced presence of endothelial insulin receptor alpha and inward remodeling
Authors: Lazo-Fernandez Yoskaly , Padilla Jaume , Martinez-Lemus Luis A. 
Published: May 2024

Type 2 diabetes (T2D) is a major risk factor for cardiovascular disease (CVD) development and associated mortality. In the cerebral circulation, T2D-related vascular disfunction also contributes to diverse cerebrovascular diseases including stroke, cognitive impairment, and dementia. Previous research has documented that endothelial dysfunction and inward remodeling are prevalent pathophysiological characteristics of the arterial circulation in T2D. We have further documented that reduced presence of endothelial insulin receptor alpha (IRα) contributes to impaired insulin-dependent vasodilation in omental arteries from T2D patients. Herein, we tested the hypothesis that, compared to wild-type (WT) mice, diabetic db/db mice have reduced insulin-induced vasodilation of the posterior cerebral artery (PCA) in association with reduced presence of endothelial IRα and inward remodeling. We used pressure myography in isolated PCAs to assess vascular reactivity and remodeling, and confocal microscopy to determine IRα content on the endothelial surface. All reported differences are significant at P<0.05. Our results indicate that, when compared with WT controls, PCAs from db/db mice have reduced insulin-induced vasodilatory responses in association with reduced presence of endothelial IRα, inward remodeling, and increased arterial stiffness. The amount of IRβ, elastin, or collagen present in the PCAs did not differ between groups. These findings provide evidence of cerebrovascular endothelial dysfunction in the form of impaired insulin-induced vasodilation in db/db mice, a defect likely attributed to the reduced presence of endothelial IRα and associated with vascular inward remodeling. These changes may contribute to cerebrovascular disease development and progression in T2D, including stroke, cognitive impairment, and associated dementias. 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.
P311 Influences Macrophage Polarization
Authors: Boddupally Sreenu , Kasaram Pavana Jyotsna , Badri Kameswara 
Published: May 2024

Obesity is a pandemic disease that has become a serious concern worldwide. In United States, recently self-reported obesity rates of adults were escalated to 40%. In the early phase of obesity, excessive macrophage infiltration and disequilibrium of macrophage phenotypes (M1 vs. M2 or vice versa) play a critical role in the microenvironment of adipose tissue. It often leads to chronic inflammation and is a major cause for metabolic disorders including insulin resistance, type-2 diabetes, and cardiovascular diseases. P311 is an intrinsically disordered protein, contributes to adipogenesis as transcription regulator through activation of PPARγ2, master regulator of adipogenesis. However, the P311 role on the macrophage polarization was not known. Here we studied the macrophage polarization in presence of P311 using Raw 264.7 cells. Raw cells were treated with either interleukin-4 (IL4) or lipopolysaccharide (LPS) for macrophage polarization towards M2 and M1 phenotype respectively in presence and absence of P311 overexpression. Macrophage phenotypic switch was assessed using CD206 (M2 marker) and CD86 (M1 marker) expression. The dose and time dependent effects of IL4 and LPS on the expression of P311 and macrophage markers was also studied. A significant increase in endogenous P311 expression observed with IL4 treatment whereas LPS treatment showed the opposite effect. Our findings showed that the P311 overexpression promotes anti-inflammatory macrophage phenotype (M2) as indicated by the significant increase in mRNA and protein expression of CD206 when compared to empty vector (EV, pCMV) transfected control group. Further, P311 overexpression in LPS treated RAW cells significantly increased the expression of CD206, on contrary to the classical M1 polarization of LPS, compared to EV transfected cells. In addition, P311 suppressed the expression of CD86 there by facilitating macrophage switch towards anti-inflammatory phenotype in presence of LPS treatment. IL4 treatment alone increased macrophage activation towards M2 phenotype however IL4 treated P311 overexpressed cells showed further increase in CD206 expression compared to EV transfected cells. Our studies indicate that the P311 expression plays an important role in promoting macrophage polarization toward M2 phenotype. This study was supported by research funding to KB, from NIH/NIGMS #SC1GM141937. 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.
Acute Exercise Alters Skeletal Muscle DNA Methylation in Sedentary Participants
Authors: Zapata Bustos Rocio , Reed Baylee L. , Coletta Richard L. , Garcia Luis A. , DeFilippis Eleanna , Roust Lori R. , Funk Janet L. 
Published: May 2024

Skeletal muscle is a highly plastic tissue, adapting its structure and metabolism in response to various stimuli like exercise. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to an acute exercise bout in volunteers with a range of insulin sensitivities. We studied 14 sedentary participants (7 male/7 female): age = 34.5 ± 3.1 years, body mass index = 29.3 ± 1.9 kg/m2 and HbA1c = 5.3 ± 0.1 %. We performed VO2peak tests to determine exercise capacity (VO2peak = 25.5 ± 1.6 mL per Kg per minute) and euglycemic hyperinsulinemic clamps (Rd value = 5.9 ± 0.8 mg per Kg per minute) with vastus lateralis muscle biopsies before and 30 minutes after a single 48-minute exercise bout. We extracted DNA from the muscle biopsies and performed reduced representation bisulfite sequencing. After performing quality control on the sequencing data, 1,034,947 sites were included for downstream analyses. MethylSig analysis revealed 17,030 differentially methylated cytosines (DMC), 9,020 increased and 8,010 decreased. To identify biologically meaningful DMCs, we used a mean change of >10%, which resulted in 1,179 and 1,436 increased and decreased sites, respectively. Pathway analysis of the increased DMCs revealed an enrichment in efferocytosis, leukocyte transendothelial migration, and FOXO-mediated transcription of oxidative stress pathways. In addition, pathway analysis of the decreased DMCs revealed an enrichment in metabolic (type 2 diabetes/ PI3K-Akt signaling), actin cytoskeleton, integrin/extracellular matrix and calcium signaling pathways. Our study reveals that an acute exercise bout induces alterations in the DNA methylation of skeletal muscle, impacting specific pathways in individuals with varying degrees of insulin sensitivity. Notably, our findings underscore the remarkable plasticity of skeletal muscle tissue. This research was funded by the National Institutes of Health, grant number R01DK094013 (Dawn Coletta). 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.
TMEM16A in smooth muscle cells acts as a pacemaker channel in the internal anal sphincter
Authors: Lu Ping , Lifshitz Lawrence , Bellve Karl , ZhuGe Ronghua 
Published: May 2024

Maintenance of fecal continence requires a continuous or basal tone of the internal anal sphincter (IAS). Paradoxically, the basal tone results largely from high-frequency rhythmic contractions of the IAS smooth muscle. However, the cellular and molecular mechanisms that initiate these contractions remain elusive. Here we show that the IAS contains multiple pacemakers. These pacemakers spontaneously generate propagating calcium waves that drive rhythmic contractions and establish the basal tone. These waves are myogenic and act independently of nerve, paracrine or autocrine signals. Using cell-specific gene knockout mice, we further found that TMEM16A Cl− channels in smooth muscle cells (but not in the interstitial cells of Cajal) are indispensable for pacemaking, rhythmic contractions, and basal tone. Our results identify TMEM16A in smooth muscle cells as a critical pacemaker channel that enables the IAS to contract rhythmically and continuously. This study provides cellular and molecular insights into fecal continence. R01HL139686 and R21HD097458. 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.
Ca2+-dependent contractile signaling induced by dsDNA-cGAS ligation mediates type 1 interferon generation and vascular injury
Authors: Joshi Bhagwati , Joshi Jagdish Chandra , Balaji Raghunath Rao Vijay Avin , Banerjee Somenath , Yadavalli Tejabhiram , Shukla Deepak , Mehta Dolly 
Published: May 2024

Acute Lung injury (ALI) is an uncontrolled systemic inflammatory response from bacterial or viral infection. The cyclic GMP-AMP synthase (cGAS) detects cytosolic double stranded DNA (dsDNA) release from bacteria, viruses, or apoptotic cells and induces innate immunity by generating the second messenger cGAMP and activation of stimulator of interferon genes (STING). However, the mechanisms regulating cGAS activity upon binding dsDNA remain elusive. Here, we show for the first in-depth analysis of mechanisms inducing cGAS activation in using lung endothelial cells (EC) and establish its translational relevance in causing ALI using a mouse model. We show that within 15 min, dsDNA ligation with cGAS mediates its interaction with a motor protein, myosin light chain 6 (MYL6), leading to phosphorylation of MLC and actin stress fiber formation. cGAS-MYL6-mediated MLC phosphorylation required calcium release and organization of an ER-Ca2+ sensor, Stromal Interaction Molecule 1 (STIM1) as puncta. Activated STIM1 also induced cGAS tyrosine phosphorylation at Y215/242 residues via cSrc. Interfering with MYL6 or cSrc expression impaired cGAS condensation and cGAMP generation. Liposome delivery of phosphodeficient cGAS (Y215/Y242àF215/F242) in EC of cGAS null mice blocked type1-IFN production during bacterial pneumonia. Our finding suggests that STIM1 is crucial in inducing cGAS activity and type1-IFN production. cGAS thus represents a novel target for inhibiting STING activation, thereby suppressing tissue injury and inflammation. NIH. 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.
Enhancing Physiology Education Through Physiological Simulation
Authors: Fong Angelina , Kim Phillip , Rathner Joseph 
Published: May 2024

Advances in Physiology Education began publishing papers in 2005, using classic papers in physiology teaching [1]. This approach has several valuable outcomes: Classic experiments, conclusion of which form the foundation of much of our undergraduate teaching textbooks, require less specialized knowledge to understand and interpret the data and conclusions. It demonstrates the scientific method, demonstrating both "what do we know" and "how do we know." It promotes inquiry-based learning. It fosters data literacy, teaching students to interpret graphs and provides historical context for physiology [1]. Traditional practical classes achieve many of these outcomes while also providing a tactile experience, and have added benefits to students’ data literacy — in as much as the students perform the protocols themselves. Students will gain insight to what “squiggly lines” on a screen are measuring and the individual variability in what raw physiological recordings look like. Students will gain a greater appreciation for analytical techniques, and the manipulations and analysis that needs to be performed to interpret data. Students also gain an appreciation of the difference between textbook vs real data. Nevertheless, in person practical classes have limitations due to resource intensity, including space, materials, and curriculum time. HumMod (hummod.org) is a freely available mathematical model of Human Physiology, a "time-dependent physiologic simulation engine" [2]. JustPhysiology (justphysiology.com) is an education-focused web interface for HumMod [3]. We have written four physiology-based workshops utilizing simulated data from JustPhysiology. The JustPhysiology workshops were setup as a structured inquiry activity where students are expected to apply their content knowledge to interpret data, and students submitted their reports after each workshop for evaluation and feedback. In preparing the workshop activities for deployment, we trialed the activities with students who had previously completed our second year Human Physiology subject (and were thus familiar with the content). We then engaged students in focus group interviews —ascertaining the students’ perceptions of the learning experience. The outcome of the focus group interview suggests that students engaging with the workshop tasks enter into a positive learning cycle: [Formula: see text] The spontaneous emergence of a learning cycle, promoting deeper understanding of the physiology suggests that these data driven workshops will have improve student learning in Human Physiology. References:DOI: 10.1152/advan.00031.2005; DOI: 10.1146/annurev-bioeng-082219-051740; DOI: 10.1016/j.morpho.2019.09.004. University of Melbourne FlexAP initiative. 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.