bluuebunny/crossref_metadata_2025_split huggingface dataset:
PYY regulates human skeletal muscle progenitor cell proliferation
Authors: Gheller Brandon JF , Roman Heather A , Thalacker‐Mercer Anna E 
Published: November 2023

Adult skeletal muscle stem cells (satellite cells) are required for regeneration after injury. The regulation of regeneration has not been fully elucidated, but relies on factors both intrinsic and extrinsic to the satellite cells. Identifying and characterizing factors that influence satellite cell proliferation is necessary for the development of therapies to aid with muscle‐related disorders. We have recently shown that peptide YY (PYY) is temporally expressed and likely synthesized in differentiating muscle progenitor cells (MPCs). The function(s) of intrinsic or extrinsic PYY in MPCs is currently unknown. PYY is a ligand for the Y receptors. Activation of the Y receptors has been shown to allow stem cells to remain in a proliferative state even in the absence of fibroblast growth factor (FGF), a critical proliferative regulator.ObjectiveOur objectives were 1) to determine the PYY protein levels over time in proliferating MPCs, and 2) to evaluate the effect of exogenous PYY on human MPC proliferation in the presence and absence of FGF.MethodsHuman MPCs were obtained from 4 young female donors via vastus lateralis muscle biopsies. MPCs were sorted to produce a homogenous culture. MPCs were maintained in the proliferative state in a growth media (GM) containing Ham's F12, 20% fetal bovine serum, and 5 ng/mL bFGF. Study 1: MPCs were grown in GM. PYY protein levels were measured by an In‐Cell Western™ assay on days 5, 6, and 7 of proliferation. Study 2: Three days after seeding MPCs in GM, cultures were switched to one of four media: 1) GM with 5 ng/mL bFGF (CON); 2) GM without bFGF (noFGF); 3) GM with a physiologically relevant dose of PYY (500 pM) but without bFGF (Norm‐PYY); 4) GM with a supra‐physiological dose of PYY (1 nM) but without bFGF (High‐PYY) and grown for an additional 4 days. Using the Celigo® Cell Imaging Cytometer, percent confluence was tracked daily. On days 5, 6, and 7, MPCs were stained to identify the number of nuclei and the number of dead cells.ResultsPYY protein levels were detectible in MPCs at days 5, 6, and 7 of proliferation. PYY levels were lower on day 7 compared to days 5 (p<0.001) and 6 (p<0.001). Percent confluence area under the curve (days 2–7) was greater in Norm‐PYY compared to both CON (p<0.01) and noFGF (p<0.05) but not High‐PYY. After 7 days of proliferation noFGF cells had fewer nuclei than CON (p<0.05) showing that removal of bFGF reduced proliferative ability of MPCs. In Norm‐PYY, nuclei count was greater (day 7) than noFGF (p<0.001) but not different from CON suggesting that PYY rescued the proliferative ability that was lost when FGF was removed from the media.ConclusionMPCs likely synthesize PYY throughout proliferation in a temporal fashion that may be related to the proliferative capacity of the cell. PYY exerts a pro‐proliferative effect on MPCs in culture, possibly, through a mechanism similar to FGF.Support or Funding InformationCornell University, Canadian Institute for Health Research Doctoral Foreign Study Award
Regulated in Development and DNA Damage 1 (REDD1) Alters the Expression of a Distinct Set of Genes in Skeletal Muscle by Activity/Inactivity
Authors: Gordon Bradley Scott , Steiner Jennifer Lynn , Williamson David , Coen Paul , Rossetti Michael , Shyamalagovindarajan Subramaniam , Eroshkin Alexey 
Published: November 2023

Regulated in Development and DNA Damage 1 (REDD1) is a stress induced protein implicated in a variety of physiological and pathological conditions. While the most highly characterized role of REDD1 is its regulation of signaling through the mechanistic target of rapamycin in complex 1, recent work indicates that REDD1 may also act to modulate gene expression patterns in skeletal muscle. Interestingly, REDD1 expression is highly induced in skeletal muscle following a single bout of aerobic exercise; a stimulus known to alter gene expression. To shed further light on the consequence of REDD1 expression by activity/inactivity, REDD1+/+ and REDD1−/− mice were randomized to remain sedentary or subjected to a single bout of aerobic treadmill exercise. Mice subjected to exercise were allowed to recover for 1, 3, or 6 hr. In the plantaris of REDD1+/+ mice, REDD1 protein expression increased 907% and 201% at 1 hr and 3 hr post exercise, respectively, before returning to near baseline levels 6 hrs post exercise. As REDD1 induction was greatest 1 hr post exercise, total RNA of the plantaris from sedentary and 1 hr post exercise REDD1+/+ and REDD1−/− mice was subjected to microarray analysis. Comparison of the gene expression patterns in the muscle of sedentary mice identified 201 genes that were differentially expressed by disruption of REDD1. Specifically, qRT‐PCR analysis confirmed that the gene expression of Park2 and Ucp1, genes implicated in mitophagy and oxidative phosphorylation, were reduced by 50% and 84%, respectively, by the disruption of REDD1. Interestingly, following a bout of exercise, the microarray detected REDD1 as the gene with the greatest exercise‐induced magnitude of change in REDD1+/+ mice. Further analysis of genes altered by the absence of REDD1 in the plantaris of exercised mice revealed significant changes in 23 genes with functions related to muscle endurance, inflammation, and muscle metabolism. Subsequent qRT‐PCR analysis confirmed that the gene expression of Malt1 and Orm1 were decreased by 47% and 53%, respectively, while the gene expression of Arrdc3 was enhanced by 93% by disruption of REDD1 1 hr post exercise. Despite changes in these genes, qRT‐PCR confirmed that the induction of Peroxisome Proliferator Activated Receptor Gamma Coactivator 1 alpha (PGC‐1α), a well‐known gene induced by exercise, was unaffected by the loss of REDD1. In all, these data support a role for REDD1 in the regulation of a distinct set of genes by activity/inactivity.Support or Funding InformationNIH grant F32 AA023422 (JLS)
Optogenetic Activation of AgRP Neurons Lengthens and Deepens Daily Torpor in the Mouse
Authors: Vicent Maria A , Mook Conor L , Carter Matthew L , Swoap Steven John 
Published: November 2023

In response to food scarcity and low ambient temperatures, mice enter bouts of torpor resulting in energy conservation. During a torpor bout, mice exhibit a substantial decrease in body temperature (Tb), heart rate (HR), and metabolic rate. The neurobiology of torpor is largely unknown. It has been shown that peripheral administration of ghrelin, a stomach‐derived hormone released during energy deprivation, to calorically restricted mice deepens and lengthens torpor bouts. It is thought that ghrelin induces its physiological effects by activating Agouti‐related protein (AgRP) containing neurons in the arcuate nucleus of the hypothalamus. Therefore, we hypothesized that direct stimulation of AgRP neurons would decrease the minimum Tb of torpid mice and increase the time spent in torpor. To test this hypothesis, mice were implanted with ECG/Tb telemeters and hypothalamic AgRP neurons were selectively targeted with the light‐sensitive channelrhodopsin‐2 transgene. Mice were calorically restricted daily (65% of normal caloric intake) until regular daily torpor bouts were achieved. On baseline days, when AgRP neurons were not activated, minimum Tb was 25.6 ± 0.8 °C and time in torpor was 233 ± 34 minutes. When AgRP neurons were stimulated for one hour during entry into torpor (20 Hz for 1 second every 4 seconds for 60 minutes), minimum Tb was significantly lower (22.8 ± 0.3 °C) and torpor bouts were significantly longer (435 ± 29 min). These data support the hypothesis that AgRP neurons directly regulate torpor physiology and begin to elucidate the neural circuits responsible for torpor regulation.Support or Funding InformationSupported by 1R15HL120072‐01A1 to SJS and by 1R15DK105510 to MC
Heat therapy alters the expression of myogenic and angiogenic factors and accelerates functional recovery following exercise‐induced muscle damage in humans
Authors: Kim Kyoungrae , Nie Yaohui , Boersma Doug , Song Qifan , Kuang Shihuan , Gavin Timothy P. , Roseguini Bruno T. 
Published: November 2023

IntroductionExposure to a single session of heat therapy (HT) promotes the mRNA expression of pivotal angiogenic and inflammatory mediators in human skeletal muscle. We investigated the effects of repeated HT on functional recovery and the expression of select genes involved in myogenesis, angiogenesis and inflammation following exercise‐induced muscle damage (EIMD).MethodsEleven healthy young adults (23.8±0.6yrs, BMI 23.7±0.6) performed 300 maximal eccentric contractions of the knee extensors with both legs. One randomly selected thigh was treated with HT immediately after the exercise bout and 4 additional consecutive days while the opposite thigh served as a control. A water‐circulating garment perfused with water at ~52°C was used to apply HT for 90 min. Thermoneutral water (33°C) was circulated through the garment in the control thigh. Biopsies from the vastus lateralis muscle were obtained 2 weeks prior to and 1 and 5 days after the eccentric exercise bout. The mRNA expression of myogenic, angiogenic and inflammatory factors was determined using real‐time polymerase chain reaction. Perceived pain (visual analog scale) and fatigue resistance (total work amount during 28 repetition maximums at 180°/s) were assessed before, during and after the intervention.ResultsA similar reduction in fatigue resistance (Control: −27.1±3.7% vs. HT: −21.4±4.6%, p>0.05) and an increase in perceived muscle pain (Control: 4.3±0.7 vs. HT: 4.2±0.7, p>0.05) were observed in both legs 1 day after the exercise bout. However, the thigh treated with HT had greater fatigue resistance than the control thigh (Control: −15.9±2.8% vs. HT: −9.6±1.9%, p=0.04) 4 days after the EIMD protocol. Perceived muscle pain was also lower in the thigh exposed to HT at 4 (Control: 2.9±0.6 vs. HT: 2.3±0.4, p=0.02) and 5 days (Control: 1.8±0.4 vs. HT: 1.3±0.3, p=0.02) after the exercise bout. When compared to the control thigh, the change in mRNA expression from baseline of paired box 7 (Control: 0.9±0.1 vs. HT: 1.3±0.1, p=0.04), vascular endothelial growth factor (Control: 0.8±0.1 vs. HT: 1.2±0.1, p<0.01), and angiopoietin 1 (Control: 0.3±0.1 vs. HT: 0.5±0.1, p=0.02) was higher in the thigh exposed to HT 1 day after the exercise bout. After 5 consecutive days of HT, the change in mRNA expression from baseline of monocyte chemoattractant protein 1 (Control: 1.3±0.3 vs. HT: 0.5±0.1, p<0.01) and myostatin (Control: 0.6±0.1 vs. HT: 0.3±0.1, p<0.01) were significantly lower in the thigh treated with HT.ConclusionTaken together, these results suggest that application of HT accelerates functional recovery following EIMD in humans, possibly by enhancing the expression angiogenic and myogenic factors early in the repair process.
Alterations of Mitochondrial Function and Metabolism in Skeletal Muscle, Liver, and White Adipose: Early Evidence for the Lactation Reset Hypothesis
Authors: Hyatt Hayden W , Zhang Yufeng , Hood Wendy R , Kavazis Andreas N 
Published: November 2023

Lactation following reproduction serves as one of the largest metabolic challenges a female experiences in their lifetime. As such, the lactation reset hypothesis has been proposed to explain changes in metabolism that confers protective health benefits (e.g., fewer visceral adipocytes, lower fasting glucose, increased insulin sensitivity, etc.) in mothers that breast‐feed their children.PURPOSEThe aim of the current experiment was to discern mitochondrial function differences and changes in markers of metabolism in female rats that nurse their pups to weaning compared to rats that reproduce but do not nurse their pups or do not reproduce.METHODSFemale Sprague‐Dawley rats were assigned to one of three groups: 1) gave birth and nursed their pups for 21 days and were sacrificed seven days later (PL), 2) age‐matched that gave birth but had pups removed and thus did not nurse (P), and 3) age‐matched that did not reproduce (NR). Liver and skeletal muscle were dissected immediately following sacrifice and mitochondria were isolated using differential centrifugation for measurements of respiration utilizing high resolution respirometry. Liver, skeletal muscle, and white adipose tissue were stored for western blot analysis.RESULTSLiver mass was higher in PL compared to NR (p<0.01) and P (p=0.03). PL and P exhibited higher state 3 respiration in liver mitochondria when utilizing complex I substrates (i.e., pyruvate and malate) compared to NR (p=0.03 and p=0.05, respectively). Noteworthy, PL demonstrated lower respiratory control ratio in liver mitochondria when utilizing complex II substrates compared to NR (p=0.03) and P (p=0.02). No differences in skeletal muscle mitochondria respiration were detected (p>0.05). Protein levels of superoxide dismutase 2 (SOD2) in the liver were higher in PL compared to NR (p=0.01) and P (p=0.05). Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1a) protein was higher in liver of PL compared to NR (p<0.01) and higher in P compared to NR (p=0.05). Catalase (CAT) protein levels in liver were higher in P (p=0.04) and PL (p=0.05) compared to NR. There were no differences in superoxide dismutase 1 (SOD1), glutathione peroxidase (GPX), and peroxisome proliferator activated receptor delta (PPAR‐δ) protein expression (p>0.05) in liver. WAT protein expression of PPAR‐d was higher in PL animals compared to NR (p<0.01) and P (p=0.05). No differences (p>0.05) were observed in WAT protein expression for GPX, CAT, SOD1, SOD2, PGC‐1a.CONCLUSIONThe taxing metabolic event of lactation produces systemic alterations in metabolism and liver mitochondrial function that persist a week after the cessation of nursing in rats, which may, in part, explain the beneficial effects of breast‐feeding.Support or Funding InformationFunded by NIH R03HD083654
Cardiac baroreflex sensitivity during lower body negative pressure and acute hypoxia: fainters vs. nonfainters
Authors: Aarts Hugo M. , Petersen‐Jones Humphrey G. , Johnson Blair D. , Curry Timothy B. , Joyner Michael J. 
Published: November 2023

BackgroundHypoxia increases susceptibility to syncope during orthostatic stress. Furthermore, cardiac baroreflex sensitivity (cBRS) is attenuated during lower body negative pressure (LBNP). Recent studies suggest that there is cross‐talk between baroreceptors and carotid body chemoreceptors. With this in mind, hypoxia may further blunt cardiac baroreflex sensitivity (cBRS) during central hypovolemia in individuals susceptible to hypoxic syncope.Therefore, we hypothesized that participants susceptible to hypoxic syncope (“fainters”) during progressive central hypovolemia would have lower spontaneous cBRS during LBNP when compared to “nonfainters”.MethodsTen healthy male participants (35 ± 3 yr, BMI 25 ± 1 kg/m2) were exposed to stepwise lower body negative pressure (LBNP, 5 minutes at 0, −15, −30, −45 mmHg) during both normoxia and hypoxia (FiO2 = 0.12 – 0.15; SpO2 ~85%). LBNP protocols were terminated early if participants developed presyncopal symptoms. Data from uncompleted stages were excluded. Heart rate (HR, 3 lead electrocardiogram) and mean arterial blood pressure (MAP, brachial arterial catheter) were continuously recorded. Spectral cBRS was calculated from the heart rate and blood pressure signals. Following experimentation, participants were stratified as fainters (developed presyncopal symptoms during hypoxic conditions, n=7) and nonfainters (n=3).ResultsMAP was lower in fainters than in nonfainters during hypoxia (interaction with LBNP p<0.05) while HR (p=0.38) and cBRS (p=0.43) were similar – Table 1. Hypoxia had a main effect vs normoxia on MAP, HR and cBRS in fainters (all p<0.02). In nonfainters hypoxia had a main effect vs normoxia on HR and cBRS (all p<0.03) and an interaction effect with LBNP on MAP (p<0.01).ConclusionSpontaneous cardiac baroreflex sensitivity is not attenuated in participants susceptible to hypoxic syncope during lower body negative pressure. This suggests that spontaneous cardiac baroreflex sensitivity does not contribute to orthostatic intolerance during hypoxia.Support or Funding InformationFunding: W81XWH‐13‐2‐0038
Physiological response in fainters and nonfainters to LBNP during hypoxia and normoxia

MAP, mmHg
HR, beats·min−1
cBRS, ms·mmHg−1

Nonfainters
Fainters
Nonfainters
Fainters
Nonfainters
Fainters

Baseline

Normoxia
104 ± 5
102 ± 3
62 ± 5
61 ± 3
13 ± 3
19 ± 2

Hypoxia
106 ± 6
97 ± 4
80 ± 6
72 ± 4
9 ± 3
11 ± 2

LBNP −15 mmHg

Normoxia
109 ± 5
103 ± 3
68 ± 5
64 ± 3
11 ± 3
14 ± 2

Hypoxia
106 ± 6
90 ± 4
88 ± 6
72 ± 4
9 ± 3
14 ± 2

LBNP −30 mmHg

Normoxia
107 ± 5
98 ± 3
79 ± 5
74 ± 3
8 ± 3
11 ± 2

Hypoxia
103 ± 6†
82 ± 5*
95 ± 6
79 ± 5
8 ± 3
9 ± 3

LBNP −45 mmHg

Normoxia
101 ± 5
99 ± 3
92 ± 5
84 ± 4
6 ± 2
5 ± 2

Hypoxia
89 ± 6†
N/A
113 ± 6
N/A
3 ± 3
N/A

Different vs. nonfainters p<0.05
Different vs. normoxia p<0.05
A novel rat model of orthopedic trauma for prehospital pain studies
Authors: Xiang Lusha , Avila Martha M , Klemcke Harold G , Ryan Kathy L , Hinojosa‐Laborde Carmen 
Published: November 2023

Animal models of orthopedic trauma usually consist of tibia or femur fractures that require a post‐fracture fixation surgery. Such an approach compromises subsequent assessments of pain following orthopedic trauma. The goal of the current study was to establish a rat model of long bone fracture that needs no post‐trauma surgeries, thereby optimizing its utility for future studies especially with prehospital pain management. Orthopedic trauma, including soft tissue injury and fibula fracture, was performed on the right hindlimb in Sprague Dawley rats. Soft tissue injury was induced in anesthetized rats via clamping the retrofemoral tissue groups for 30 sec, followed by closed fibula fracture using a 15‐gauge needle. Thermal hyperalgesia (paw withdrawal time, PW, n = 24), mechanical allodynia (mechanical threshold, MT, n = 17), weight‐bearing ratio (right/left, WB, n = 12), and tail flick latency (n = 10) were determined before and 90 minutes after the injury. Rats were then treated with 5 mg/kg ketamine or vehicle (saline) through jugular catheters, and nociceptive measurements were repeated at 10, 40, 80, and 120 minutes after injection. Trauma had no effect on tail flick responses but decreased PW, MT, and WB (Table 1). Ketamine increased PW, WB, and tail flick latency mainly within the first 40 minutes following injection (Figure 1). As no post‐trauma surgery is required, our data suggest that this trauma model may be ideal for prehospital pain research. To our knowledge, this is the first study to show that 5 mg/kg of ketamine iv could be considered for instant analgesia in rats.
Thermal hyperalgesia (PW), mechanical allodynia (MT), weight‐bearing ratio (WB), and tail flick response before and after trauma.

PW (second)
MT (gram)
WB (right/left)
Tail flick (second)

Basal
11.3±0.5
40.5±1.5
1.0±0.1
5.6±0.2

Trauma
6.5±0.2*
31.7±2.3*
0.5±0.1*
5.6±0.1

P < 0.05 trauma vs. basal.
Anti‐Retroviral Therapy Increases Hepatic Gluconeogenic and Lipogenic Enzyme Expression but does not Alter Expression of Insulin Signaling Cascade Proteins in Chronic Binge Alcohol‐Administered SIV‐Infected Rhesus Macaques
Authors: Ford Stephen Michael , Nelson Steve , Bagby Gregory J. , Simon Liz , Molina Patricia E. 
Published: November 2023

Chronic alcohol consumption, HIV infection, and anti‐retroviral therapy (ART) have independently been shown to increase risk for metabolic dysregulation. Previously we demonstrated that chronic binge alcohol (CBA) administration to simian immunodeficiency virus (SIV) infected male rhesus macaques impaired glucose‐insulin dynamics at 11 months post‐SIV infection. This was reflected in reduced acute insulin response to a glucose load, and decreased whole body glucose effectiveness, a measure of the rate of systemic glucose disappearance. The aim of this study was to determine whether CBA and/or ART altered hepatic gene expression of gluconeogenic and lipogenic enzymes and insulin signaling proteins in association with our previous findings of CBA‐mediated impairments in whole body glucose‐insulin dynamics. CBA or sucrose (SUC) was administered intragastrically through a surgically implanted indwelling catheter beginning at 3 mos prior to infection with SIVmac251 (and continued for the duration of the study) in male rhesus macaques. At 2.5 mos. post‐SIV infection, daily administration of ART was initiated in half of the SUC/SIV and CBA/SIV macaques. At necropsy (11 mos post‐SIV infection), livers were collected for analyses of mRNA and protein expression. Liver from ART‐treated SIV‐infected macaques showed increased mRNA expression of phosphoenolpyruvate carboxykinase‐1 (PEPCK‐1), glucose‐6‐phosphatase (G6Pase), and acetyl CoA carboxylase (ACC), compared to that of ART‐negative macaques, irrespective of CBA or SUC administration. Neither CBA nor ART administration altered hepatic protein expression of phosphatase and tensin homolog (PTEN) or protein tyrosine phosphatase 1B (PTP1B), phosphatase enzymes that attenuate insulin signaling. In addition, neither CBA nor ART reduced insulin signaling as determined by the ratio of phosphorylated/total protein expression for mTOR (S2448) and Akt (S473). ART‐treated animals showed higher P‐AMPK (T172)/total AMPK ratio irrespective of SUC or CBA administration, compared to ART‐negative animals. These findings suggest that ART contributes to impaired anabolic metabolism in an organ‐specific manner. Ongoing studies will demonstrate whether CBA and/or ART adversely affect(s) catabolic pathways of metabolism, including the glycolytic pathway. Taken together, our data suggest that chronic alcohol and ART may act synergistically to potentiate the progression of metabolic dysregulation in people living with HIV/AIDS.Support or Funding InformationThe work was supported by National Institutes of Health (NIH) grants: P60AA09803, T32AA07577, and F30AA024030‐01A1.