bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Alpha‐Adrenergic Vasoconstriction in Regulating Skeletal Muscle Blood Flow during Single Leg Knee Extension Exercise with Advancing Age
Authors: Ratchford Stephen M , Clifton Heather L , Barret‐O'Keefe Zachary M , Broxterman Ryan M , Gifford Jayson R , Hydren Jay R , Rossman Matthew J , Ives Stephen J , Trinity Joel D , Witman Melissa AH , Garten Ryan S , Morgan David E , Nelson Ashley D , Richardson Russell S , Wray David Walter 
Published: November 2023

BackgroundAging is associated with augmented sympathetic nervous system activity, which promotes vasoconstriction in the peripheral circulation through the alpha‐adrenergic pathway. However, whether this age‐related sympathoexcitation restrains exercising skeletal muscle blood flow and vascular conductance remains poorly understood.MethodsIn nine young (4F/5M, 25 ± 5 yr, 178 ± 8 cm, 73 ± 12 kg) and seven old (2F/5M, 63 ± 11 yr, 175 ± 9 cm, 78 ± 15 kg) healthy volunteers, we evaluated changes in leg blood flow (LBF, Doppler ultrasound), mean arterial pressure (MAP) and leg vascular conductance (LVC) before and after femoral intra‐arterial infusion of phentolamine (a nonselective alpha‐adrenergic antagonist) at rest and during knee‐extensor exercise (0, 5, and 10W). Results are presented as the change from control to adrenergic blockade conditions.ResultsAt rest, similar increases in LBF (269 ± 45 vs. 250 ± 60 ml/min, young vs. older) and LVC (3.4 ± 0.6 vs. 2.9 ± 0.6 ml/min/mmHg, young vs. old) were observed between groups following the adrenergic blockade. During exercise, the adrenergic blockade increased LBF to a similar degree in both young (0W: 330 ± 116, 5W: 178 ± 130, and 10W: 239 ± 127ml/min) and old (0W: 209 ± 57, 5W: 251 ± 22, and 10W: 165 ± 75 ml/min), with no difference between work rates in either group. Similarly, LVC increased as a consequence of the adrenergic blockade in both young (0W: 4.6 ± 1.2, 5W: 3.0 ± 1.2, and 10W: 3.1 ± 1.2 ml/min/mmHg) and old (0W: 3.6 ± 1.1, 5W: 4.2 ± 0.9, and 10W: 3.8 ± 0.9 ml/min/mmHg), with no difference between work rates. Both at rest and during exercise, MAP did not differ between groups or as a consequence of drug administration.ConclusionsUsing a pharmacologic approach to locally block alpha adrenergic vasoconstriction, we observed a similar drug‐induced change in leg hemodynamics in both the young and old groups. These data suggest that sympathetic restraint of limb blood flow persists during small muscle mass exercise, and that this adrenergic response is not impacted by advancing age.Support or Funding InformationFunded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001697, RX001418, E6910R).
Revisiting “Resetting” of Baroreflexes During Canine Exercise
Authors: Wurster Robert D. 
Published: November 2023

At rest and during exercise, systemic arterial blood pressure(SAP) is regulated by classic arterial baroreceptor reflexes mediated by receptors located largely in the carotid sinus(CS) and the ascending aorta. Many investigators have concluded that exercise causes these controls to be “reset” to higher pressures.Presently, changes of SAP and heart rate(HR) during treadmill exercise (up a 10% grade) were investigated using 5 exercise‐trained dogs that were surgically instrumented with a bilateral, vascularly‐isolated CS preparation and aortic nerve denervations. This allows systematic, stepwise changes of CS pressures(CSP) (25 mm Hg steps between 50 and 200 mm Hg) independent of SAP changes and at various exercise levels (5 min. steps from 0 to almost 10 Km/hr) without involvement of the aortic baroreceptors.At all levels of exercise, SAP responses to CSP's below 100 mm Hg were nearly identical. At low exercise levels (3.2 Km/hr), SAP changes at all CSP's (50 to 200 mm Hg) remained unaltered compared to at rest. However, with higher exercise levels at higher CSP's (from 100 to 200 mm Hg), changes in SAP became greatly attenuated.On the other hand, HR changes occurred with every change in exercise level, regardless of the CSP. At rest, changes in HR occurred with every rise or fall of CSP. However, during exercise, HR responses to CSP changes above 100 mm Hg were markedly attenuated, especially at higher CSP's.These data suggest that baroreflex control of SAP is not significantly altered by the exercise intensity, suggesting little role of central command and mechanoreflex resetting. However, metaboreflexes limit minimal levels of SAP, resulting in elevation of SAP at higher exercise levels. Baroreflex control of HR is influenced by higher levels of exercise, suggesting a “resetting” role of central command and/or mechanoreflexes. Similar to SAP control, the minimal HR responses are limited by activation of metaboreflexes resulting in higher HR responses at all CS pressures. In conclussion, CS reflex control of SAP and HR during exercise are different but have in common the influences of metaboreflexes.Support or Funding InformationPublic Health Service Grant HL 08682
AdipoRon, pan‐adiponectin receptor agonist, activates mitochondrial metabolism via AMPK‐PGC1α pathway in the skeletal muscle
Authors: Balasubramanian Priya , Howell Porsha , Martin Stephen , Anderson Rozalyn 
Published: November 2023

Adiponectin is an adipose tissue‐derived peptide multimer that impinges on skeletal muscle cellular metabolism to activate lipid utilization and mitochondrial oxidative pathways. The actions of adiponectin resemble exercise in that adiponectin signaling activates AMPK and PGC1α downstream of AdipoR1 and R2 receptor in the skeletal muscle. It is known that interventions that increase PGC1a in the skeletal muscle enhance endurance and protect against muscle aging. AdipoRon is a recently identified pan‐adiponectin receptor agonist. We hypothesize that activation of adiponectin receptor using AdipoRon will activate PGC1α and mitochondrial metabolism in the skeletal muscle. Our results show that AdipoRon increases phosphorylation of AMPK (Thr172) and its downstream target acetyl‐coA carboxylase (ACC) within 10 minutes of treatment both in cells (NIH 3T3 fibroblasts and primate peripheral blood mononuclear cells (PBMCs)) and in skeletal muscle of treated mice. AdipoRon treatment also caused an increase in the expression of gene targets of PGC‐1a involved in lipid metabolism namely Cpt1a, Acadm and Acox1 both in cells and in skeletal muscle of AdipoRon treated mice. Interestingly, the effects of AdipoRon were fiber‐type specific as the transcriptional changes were only observed in gastrocnemius muscle with predominantly type II glycolytic fibers that are more vulnerable for aging and not in soleus enriched for type I oxidative fibers. Chronic AdipoRon treatment also resulted in the up regulation of genes involved in mitochondrial fusion process, Mfn1 and Mfn2, suggesting its involvement in modulating mitochondrial dynamics to facilitate oxidative metabolism. Further investigations are needed to determine the precise metabolic consequence of adiponectin receptor activation by AdipoRon and to determine the therapeutic potential of this promising new drug to modulate the processes implicated in skeletal muscle aging.Support or Funding InformationSupported by NIHAG047358
Satellite Cell‐Mediated Myonuclear Accretion Is Required For Mechanical Overload‐Induced Hypertrophy In Young Growing Mice
Authors: Murach Kevin , White Sarah , Wen Yuan , Ho Angel , Kosmac Kate , McCarthy John , Peterson Charlotte 
Published: November 2023

When skeletal muscle hypertrophy is induced by mechanical or genetic means, numerous investigations report that satellite cell‐mediated myonuclear accretion is not required to promote muscle growth in adult mice (≥16 weeks old). However, recent evidence suggests that the satellite cell requirement during hypertrophy is influenced by maturational age. That is, if a hypertrophic stimulus is imposed on growing muscle during adolescence, satellite cell‐mediated myonuclear accretion may become necessary to support the additional growth. The purpose of this investigation was to rigorously test whether maturational age alters the requirement for satellite cell‐mediated myonuclear accretion during mechanically‐induced skeletal muscle hypertrophy. Using the Pax7CreR‐R26RDTA mouse, we conditionally depleted satellite cells in adolescent mice (8 weeks of age) via five consecutive daily tamoxifen injections, then allowed a two‐week washout (SC−). Age‐matched vehicle‐treated Pax7CreR‐R26RDTA mice were used as controls (SC+). Tamoxifen‐ and vehicle‐treated mice were then sham surgerized or synergist ablated for 10 days via a modified technique that overloads the plantaris muscle but minimizes muscle regeneration (n=6–8 per group). Satellite cell density (Pax7+ cells/fiber), embryonic myosin heavy chain expression (eMyHC), and muscle fiber cross sectional area were evaluated via immunohistochemistry. Myonuclear counts (myonuclei/100 millimeters) were performed on isolated single muscle fibers. Only tamoxifen‐treated mice with ≥90% satellite cell depletion were included in this analysis. Following 10 days of mechanical overload of the plantaris, SC+ mice experienced a 60% increase in satellite cell density (P<0.05). Muscle fiber cross sectional area and myonuclear number increased by 20% in SC+ (P<0.05), but did not change in SC− mice (P>0.05). Expression of eMyHC across all mice was <2%, indicating that overload surgery did not induce a regenerative response. Resident myonuclei of young growing mice appear inherently different than those of adult mice in their ability to compensate during hypertrophy without satellite cells.Support or Funding InformationNIH RO1 AR060701 07
Fn14 Expression is Lower in Female Compared to Male Skeletal Muscle, Independent of Adult Age
Authors: Blum Jamie , Roman Heather , Thalacker‐Mercer Anna 
Published: November 2023

BackgroundTweak, a pro‐inflammatory cytokine, and its receptor, Fn14, are recognized as important inflammatory mediators. In skeletal muscle (SkM), elevated TWEAK signaling is associated with reduced insulin sensitivity, reduced mitochondrial biogenesis and SkM atrophy. Further, TWEAK signaling is dysregulated with aging, underlying SkM deterioration and pathological remodeling. Several studies suggest a relationship between estrogen and TWEAK signaling, such that estrogen increases TWEAK expression while suppressing Fn14 expression. Sex‐specific differences in SkM TWEAK and Fn14 have not be identified, but are likely relevant for SkM health in aging.ObjectivesWe sought to evaluate whether SkM of young females has lower Fn14 and higher TWEAK expression compared to young males, and whether Fn14 and TWEAK changes with age in both sexes.MethodsSkM biopsies were collected from the vastus lateralis of young (n=5) and old females (n=6) and young (n=6) and old males (n=4). RNA was extracted from biopsy tissue using TRIzol reagent. Gene expression was measured using qPCR. In a follow‐up experiment human myogenic progenitor cells (MPCs) were isolated from young females (YF‐MPC, n=5) and young males (YM‐MPC, n=6). Cells were cultured in Ham's F12 supplemented with 20% FBS and 5ng/ml bFGF (GM). Once cells reached 75% confluence, all cultures were switched to differentiation media [(DM), Ham's F12 + 2% HI equine serum]. MPCs were cultured in DM for 72 hours and then continued in DM for an additional 48 hours with or without 10ng/ml TNFα. RNA was isolated and gene expression measured using qPCR.ResultsAt the whole tissue level, females had a 2.86 fold lower Fn14 expression (p<0.05) and 1.34 fold higher TWEAK expression (p<0.05) compared males, independent of age. In response to TNFα treatment, differentiated YF‐MPC experienced a 1.7 fold increase in Fn14 expression (p<0.05) while no change in Fn14 expression was observed in differentiated YM‐MPC. TNFα treatment did not affect TWEAK expression in either differentiated YF‐ or YM‐MPC (p>0.05).ConclusionAs hypothesized, females have lower expression of Fn14 and higher expression of TWEAK in skeletal muscle, likely driven, in part, through estrogen‐related mechanisms. However, differences in Fn14 and TWEAK were not differential with age in the female SkM. The young female SkM was collected when the participants had low levels of estrogen, which could partially explain why we observed no difference with age in the females. Intriguingly, TNFα induced Fn14 in differentiated YF‐MPCs, but had no effect in differentiated YM‐MPCs. The significance of this difference for pathological remodeling of skeletal muscle, especially during regeneration, requires further elucidation.Support or Funding InformationCornell University
Age‐Related Alterations in Cutaneous Vascular and Sweating Responses Depend on Sex and Types of Receptor Agonist
Authors: Fujii Naoto , McNeely Brendan D , Halili Lyra , Zhang Sarah Y , Danquah Mercy O , Kenny Glen P 
Published: November 2023

In humans, peripheral cutaneous vascular and sweating function may be altered by aging. For example, cholinergic sweating (Stapleton et al. Physiol Rep, 2(7), pii: e12078, 2014) and cutaneous vasodilation (Bruning et al. J Appl Physiol, 112 (12), 2019, 2012) are markedly lower in older relative to young adults. However, it remains unclear if aging also modulates cutaneous vasodilation and sweating in response to non‐cholinergic receptor activation, and if so, to what extent. Our recent studies show that aging does not affect cutaneous vasodilation elicited by prostacyclin in males (Fujii et al. J Physiol 594 (21), 6419, 2016) whereas in older females we observed an augmented cutaneous vasodilation (unpublished data). Therefore, the objective of this study was to determine how aging might differentially modulate cutaneous vascular and sweating responses to cholinergic and non‐cholinergic receptor activations between males and females. In this preliminary study, 8 young males (23±3 years), 10 young females (23±5 years), 12 older males (58±8 years), and 9 older females (61±9 years) were recruited. In each group, cutaneous vascular conductance (CVC, measured via laser Doppler flowmetry) and sweat rate (measured via sweat capsule) was evaluated at four intradermal forearm skin sites that perfused with the following different receptor agonists: 1) methacholine (cholinergic receptor agonist, 5 doses: 0.0125, 0.25, 5, 100, 2000 mM), 2) ATP (purinergic receptor agonist, 5 doses: 0.03, 0.3, 3, 30, 300 mM), 3) nicotine (nicotinic receptor agonist, 5 doses: 1.2, 3.6, 11, 33, 100 mM), and 4) isoproterenol (β‐adrenergic receptor agonist, 3 doses: 1, 10, 100 μM). An age‐related reduction for cholinergic sweating was observed in females (P≤0.05) but not males (P>0.05). Moreover, purinergic cutaneous vasodilation was attenuated in older relative to young adults for males only (P≤0.05). β‐adrenergic cutaneous vasodilation was greater in both older males and females as compared to their younger counterparts (P≤0.05). Furthermore, there were no age‐related differences in cholinergic cutaneous vasodilation, nicotinic cutaneous vasodilation and sweating, as well as β‐adrenergic sweating, irrespective of sex (P>0.05). Purinergic receptor activation did not elicit an increase in sweating among all groups (all P>0.05). Our results show that aging modulates cutaneous vascular and sweating responses, however this modulation is dependent on sex and types of receptor agonist.Support or Funding InformationThis study was supported by the Natural Sciences and Engineering Research Council of Canada (Discovery grant, RGPIN‐06313‐2014; Discovery Grants Program ‐ Accelerator Supplement, RGPAS‐462252‐2014; funds held by Dr. Glen P. Kenny).
Raw Garlic Aqueous Extract (RGAE) Augments MafA Expression in the Liver of STZ‐Induced Type‐1 Diabetic Rats
Authors: Al‐Qattan Khaled K , Al‐Otaibi Anood , Al‐Adsani Amani , Al‐Bader Maie , Thomson Martha , Divya SJ , Miranda Lavina , Al‐Bustan Suzanne 
Published: November 2023

BackgroundTreatment with raw garlic aqueous extract (RGAE) increases plasma insulin concentration in the rat model of streptozotocin (STZ)‐induced type‐1 diabetes mellitus (DM). The regulatory gene MafA plays an important role in insulin gene expression and production.ObjectiveThis study investigated the effect of RGAE on MafA expression in the liver of STZ‐type‐1 DM rats.MethodA group of normal rats (n=8, NR‐NS) and a group of DM rats (n=8, DR‐NS) were treated with normal saline (NS). Additionally, a group of normal rats (n=8, NR‐RGAE) and a group of diabetic rats (n=8, DR‐RGAE) were treated with RGAE. All treatments were carried out for 8 weeks after which all rats' liver and pancreas were analyzed for MafA expression at week 1 (n=4, each group) and week 8 (n=4, each group). Total mRNA was extracted from both the liver and pancreatic tissues and then converted to cDNA for gene expression profiling using real‐time PCR with Taqman assay.ResultsAt week 8 and compared to week 1, MafA expression levels in the liver did not reveal any significant changes in response to either NS or RGAE in normal rats. Alternatively, MafA expression showed differential expressions in response to RGAE treatment in the diabetic rats.ConclusionThe results indicate that RGAE may augment the expression of MafA and therefore could contribute towards the generation of insulin producing cells from the liver.Support or Funding InformationThis study was supported by The Research Sector – Kuwait University (YS04/13)
Proinsulin C‐Peptide Effects in Retinal Pigment Epithelium Health and VEGF Release: Implications for Diabetic Retinopathy
Authors: Grote Stephen M. , Kolar Grant R. , Yosten Gina L. C. 
Published: November 2023

Connecting peptide (C‐peptide) is derived from the proinsulin molecule and is released with insulin in equimolar amounts by beta cells of the pancreas. For many years, C‐peptide was known only as a marker of insulin secretion, but recent work has demonstrated that C‐peptide has important bioactivity, particularly in the microvasculature including the microvessels of the eye. In diabetic retinopathy, a leading cause of blindness in the developed world, the retinal pigment epithelium (RPE) becomes dysfunctional. The RPE normally plays vital metabolic and secretory roles in maintaining the retina through interactions with the choriocapillaris and the photoreceptor layer. However, exposure to high glucose, as in uncontrolled diabetes, may encourage transdifferentiation of RPE cells into fibroblast‐like cells that disrupt the normal functioning of this essential cell layer. Furthermore, high glucose can induce pathological hypersecretion of VEGF from the RPE, which contributes to retinopathy by stimulating retinal neovascularization and by increasing permeability of the RPE via an autocrine action. Since RPE cells express the putative C‐peptide receptor, GPR146, we hypothesized that C‐peptide in physiological concentrations might normalize RPE‐specific gene expression and inhibit VEGF release. To test this hypothesis, we first performed transdifferentiation assays using the spontaneously transformed human RPE cell line, ARPE‐19, in which cells were incubated in either high or normal glucose containing media, with or without C‐peptide for 30 days. We measured changes in gene expression of RPE functional genes using qPCR. C‐peptide enhanced expression of RPE‐specific genes, and the changes in gene expression appeared to be dependent on glucose conditions. In addition, we treated ARPE‐19 cells with C‐peptide in normal and high glucose conditions and measured VEGF secretion by ELISA. C‐peptide significantly reduced VEGF secretion; however, VEGF secretion was enhanced by treating cells with the Na+/K+ ATPase inhibitor, ouabain, suggesting that C‐peptide inhibits VEGF release by increasing Na+/K+ ATPase activity. We conclude that C‐peptide prevents transdifferentiation of RPE cells to disruptive fibroblast‐like cells by enhancing the expression of RPE‐specific genes, and that C‐peptide diminishes release of VEGF, possibly by increasing Na+/K+ ATPase activity. Future experiments exploring the mechanisms underlying these effects are essential next steps towards the development of C‐peptide‐based therapeutics for the treatment of diabetes‐associated eye disease.Support or Funding InformationHL121456 National Institutes of Health
KNOCKOUT OF MIR‐223 INDUCES BETA‐CELL DYSFUNCTION THROUGH ACTIVATION OF THE FOXO1 SIGNALING PATHWAY
Authors: Li Yutian , Peng Jiangtong , Deng Shan , Wang Xiaohong , Kuhel David , Cash James , Essandoh Kobina , Mu Xingjiang , Salem Esam , Hui David , Fan Guo‐chang 
Published: November 2023

BackgroundMicroRNAs (miRNAs) are small, endogenous non‐coding RNAs, well‐known to regulate wide ranges of biological processes and tissue metabolism homeostasis. Recently, miR‐223 has been reported to coordinate systemic cholesterol under basal conditions and ameliorate adipose tissue‐associated insulin resistance in mice fed with high‐fat diet. However, the functional role of miR‐223 in the diabetic pancreas remains less studied.Method and ResultsDiabetes was induced in C57BL6 mice (5‐week old, male) by either daily intraperitoneal injection of streptozotocin (STZ, 50μg/g body weight) for 5 days (type 1 diabetes, or T1D), or 60% high‐fat diet (HFD) feeding for 24 weeks (type 2 diabetes, or T2D). Subsequently, pancreases were collected from such diabetic mice to measure miR‐223 levels using RT‐PCR. We observed that the levels of miR‐223 were increased by 8‐fold in the T1D pancreas, and by 2‐fold in T2D pancreas, compared to respective controls. Similarly, in vitro studies using Min6 β‐cell line revealed a 3‐fold increase of miR‐223 levels upon high glucose treatment. These results indicate that miR‐223 may involve in the development of diabetes. Of important, global miR‐223 knockout (KO) mice displayed insulin resistance, as evidenced by higher levels of plasma glucose and lower levels of insulin than wild‐type (WT) mice under both basal and diabetic conditions (n=5–11, p<0.05)). Further investigation showed that the diabetic phenotype of miR‐223‐KO mice may be attributed to diminished β‐cell proliferation and increased β‐cell apoptosis. Using luciferase reporter assay, we mechanistically identified that miR‐223 could directly target the 3′‐UTR of Foxo1, a critical transcriptional factor that regulates β‐cell function and survival. Using Western‐blotting, we validated that the protein levels of Foxo1 were increased by 3‐fold in the pancreas of miR‐223‐KO mice, compared to WTs, leading to subsequent decreased levels of Pdx1 and Glut2, two key regulators of β‐cell proliferation and function.ConclusionOur study reveals that loss of miR‐223 triggers β‐cell dysfunction by post‐transcriptional activation of the Foxo1 signaling pathway, resulting in the development of diabetes.Support or Funding InformationNIH R01 GM‐112930