bluuebunny/crossref_metadata_2025_split huggingface dataset:
Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress (1160.5)
Authors: Sidossis Labros , Porter Craig , Saraf Manish , Chao Tony , Finnerty Celeste , Chondronikola Maria , Borsheim Elisabet , Hawkins Hal , Herndon David 
Published: June 2021

Intriguing new evidence from animal models suggests that white adipose tissue (WAT) can acquire a brown adipose tissue (BAT) phenotype after adrenergic stress. In this study, we investigated whether the WAT of humans has the capacity to adopt a BAT‐like phenotype (browning of WAT). Subcutaneous WAT samples were collected from 20 severely burned children (early group [8±4 days post injury] or late group [37±25 days]) and 6 healthy children (control group). Morphologic assessment of WAT from the late burn group showed numerous multilocular adipocytes that stained positive for uncoupling protein 1 (UCP1). UCP1 protein content was significantly higher in the late burn group compared to healthy controls (2.72±0.31 vs. 22.88±4.45 ng/mg, P<0.001) and the early burn group (6.88±1.39 vs. 22.88±4.45 ng/mg, P<0.01). Likewise, coupled and uncoupled mitochondrial respiration in the late burn group were 3‐fold and 4‐fold greater, respectively compared to the control group (P<0.01) and the maximum activity of citrate synthase (a proxy for mitochondrial content) of the late group was 3.7‐fold (P<0.001) higher than that in the control group. These findings sugges that the observed changes in WAT are functionally significant. To the best of our knowledge, this is the first evidence of the browning of subcutaneous WAT in humans. Our data highlight the role of WAT as a potential regulator of energy balance and metabolic control in humans.Grant Funding Source: Supported by NIH P50‐GM60338, R01‐GM05668, and Shriners Hospitals for Children (84090, 84080)
Whey protein, but not leucine ingestion reduces insulin sensitivity (1161.5)
Authors: Smith Gordon , Magkos Faidon , Klein Seth , Reeds Dominic , Bradley David , Okunade Adewole , Patterson Bruce , Klein Samuel , Mittendorfer Bettina 
Published: June 2021

Intravenous infusion of an amino acid mixture reduces insulin‐mediated glucose disposal during a hyperinsulinemic‐euglycemic clamp. The mechanisms responsible for the adverse effect of amino acids on insulin‐mediated glucose disposal are unclear and it is not known whether protein ingestion has similar adverse effects. We hypothesized that protein ingestion impairs insulin‐mediated glucose disposal due to leucine‐mediated activation of mTOR and serine‐phosphorylation of IRS1. To test this hypothesis, we conducted hyperinsulinemic‐euglycemic clamps (50 mU insulin/m2 body surface area/min) in two groups (n = 9/group) of women (age: 58±1 yr, BMI: 35±1 kg/m2) who ingested (in randomized order): a) either 0.6 g of whey protein (containing 0.0684 g of leucine) per kg fat‐free mass (28.1±1.0 g whey protein total) or placebo or b) 0.0684 g leucine per kg fat‐free mass (3.3±0.1 g leucine total) or placebo during the 4‐h clamp. Whey protein ingestion significantly reduced the rate of glucose disposal during insulin infusion (2786±324 vs. 3022±383 µmol/min, respectively, P=0.04) whereas leucine ingestion had no effect on insulin‐mediated glucose disposal (2787±212 vs. 2805±238 µmol/min, respectively, P=0.90). We conclude that: a) protein ingestion impairs insulin‐mediated glucose disposal and b) the insulin desensitizing effect of protein ingestion is not mediated by increased leucine availability.Grant Funding Source: Supported by grants from the NIH and an Ajinomoto Exploratory Research Grant.
Resveratrol and SRT1720 lead to differential effects in key metabolic organs (1162.5)
Authors: Svensson Kristoffer , Schnyder Svenia , Handschin Christoph 
Published: June 2021

Resveratrol (RSV) and SRT1720 (SRT) are postulated calorie restriction mimetic compounds, and thus are suggested to be potential pharmaceutical interventions against obesity and related metabolic complications in humans. The metabolic effects of these two compounds have been proposed to be mediated by the transcriptional co‐activator, peroxisome proliferator‐activated receptor γ co‐activator 1α (PGC‐1α), although the exact requirements for PGC‐1α in mediating these effects is still not known. Here we investigate the role of skeletal muscle PGC‐1α in mediating whole body and muscle‐specific adaptations to RSV and SRT treatment during high fat diet feeding in mice. Furthermore, we also perform a comparative analysis of the effects of these two individual compounds on metabolic processes in key metabolic organs. Using mice with a skeletal muscle‐specific deletion of PGC‐1α, we can demonstrate that PGC‐1α is necessary for transcriptional induction of mitochondrial genes in skeletal muscle, while it is dispensable for the systemic metabolic effects of both RSV‐ and SRT‐treatment. We can furthermore demonstrate both analogous and differential effects of RSV‐ and SRT‐treatment on lipid metabolism and mitochondrial biogenesis in liver as well as adipose tissue. These data provide novel insight into the metabolic effects of RSV and SRT, and thus highlight both beneficial and potential detrimental effects of these compounds when used as a therapeutic intervention for obesity.Grant Funding Source: Supported by: SNSF ‐ Swiss National Science Foundation
High protein diet and insulin effects on catabolism in rats with burns and disuse (1162.8)
Authors: Baer Lisa , Wu Xioawu , Wolf Steven , Wade Charles 
Published: June 2021

Severe burn and disuse result in metabolic alterations associated with systemic inflammatory and endocrine changes. Such changes include extreme inflammation, hypermetabolism and catabolism, resulting in dramatic endocrine shifts to enable the body to adapt to the severe burns. Using our rodent model of burn and disuse, daily insulin demonstrated improvements in total muscle and fat mass and reduced catabolism. To determine if diet can further improve these outcomes, we examined the effects of a high protein diet plus daily insulin on lean mass, blood urea nitrogen (BUN) and nitrogen balance. Male rats assigned to four groups: 20% or 40% protein diet, with or without insulin (n=6/group). Diet caloric content remained constant. Rats received a 40% TBSA scald burn and then hindlimb unloaded. Food intake and urine were collected daily for 14 days after injury. BUN levels were significantly reduced in the 20% group. A decreased nitrogen balance was observed in the 20% groups at day 3 with a steady increase over time, but remained in negative balance. The 40% groups showed a reduction by day 3 and then were in positive balance by day 14. Increased dietary protein did not improve lean, fat or muscle mass. Increased dietary protein coupled with daily insulin failed to mitigate muscle loss or catabolism in response to burn injury and disuse.Grant Funding Source: Supported by: US Army MRMC & Juvenile Diabetes Foundation
Paracrine effects of cancer on skeletal muscle: myosin loss and mitochondrial dysfunction (1163.10)
Authors: McLean Julie , Moylan Jennifer , Andrade Francisco 
Published: June 2021

Cancer cachexia is a severe skeletal muscle wasting syndrome directly responsible for 30% of all cancer deaths. Cancer exerts paracrine effects on skeletal muscle that trigger myosin loss and metabolic dysfunction. Clinical trials using cyclooxygenase 2 (COX2) inhibitors to treat cachexia had some success. Therefore, we hypothesized that tumor‐induced COX2 expression contributes to myosin loss and mitochondrial dysfunction. We incubated C2C12 myotubes with control or Lewis lung carcinoma conditioned medium (LLCCM) for 48hr. We measured protein content by western blot, and oxygen consumption rate (OCR) of intact myotubes using a Seahorse XF24. Protein content is presented as means±SD in arbitrary units (n=6/group, t test). OCR is presented in pmoles O2/min (n=8/group, repeated measures ANOVA). LLCCM treatment decreased myosin content by 70%, from 7.2±2.7 to 2.1±1 AU (p<0.01), while COX2 content increased 75%, from 1.9 ±0.1 to 3.3 ±0.2 (p<0.001). There was no significant effect on mitochondrial complex content, p >0.05 for complexes I, III, IV and V. LLCCM decreased basal OCR by 30% (p<0.003), but did not alter leak or maximal uncoupled OCR. We found that LLCCM treatment induced myosin loss and impaired mitochondrial function in C2C12 myotubes, correlating with increased COX2 content. These data support our original hypothesis, and suggest that interventions that target COX2 may be useful for cancer cachexia.Grant Funding Source: Supported by Support: NIH AR055974 (FHA).
Simultaneous reversal of age‐related declines in muscle health and cognition with transplantation of preconditioned mesenchymal stem cells (1163.2)
Authors: Huntsman Heather , De Lisio Michael , Kolyvas Emily , Merritt Jennifer , Bhattacharya Tushar , Jensen Tor , Rhodes Justin , Boppart Marni 
Published: June 2021

Mechanical strain can potently influence paracrine factor release from skeletal muscle‐derived mesenchymal stem cells (mMSCs). Since the MSC secretome has the potential to impact both local and distant tissue health, we assessed the extent to which transplanted mMSCs influence the local muscle environment as well as brain plasticity and behavior. mMSCs isolated from young muscle were preconditioned (10% multiaxial strain, 5 hrs) and immediately transplanted into the muscle of 24 month old mice. Mice receiving saline or non‐strained mMSCs served as controls. In addition to measuring indices of muscle health, the dentate gyrus of the hippocampus was evaluated for immature neurons one week post‐injection. Two weeks after transplantation, cognitive performance was measured by water maze, rotarod, and contextual fear conditioning. Although satellite cell number and fiber size were unchanged, vessel size and number of neuromuscular junctions were greater in muscle injected with strained mMSCs versus controls resulting in increased muscle function (P < 0.05). A significant increase in the number of immature neurons (P < 0.05) and a trend towards increased cognitive function on the water maze test was observed in these mice. Overall, mMSC preconditioning prior to transplantation may provide a novel method to prevent or reverse age‐related impairments in muscle strength, neuroplasticity, and cognitive function.Grant Funding Source: Supported by Ellison Medical Foundation (AG‐NS‐0547‐09), Abbott Laboraties (Abbott CNLM ZA68)
Delay in post‐ovariectomy estrogen replacement negates post‐exercise estrogen augmentation of muscle satellite cell population in rats (1163.23)
Authors: Mangan Gary , Hamilton Victoria , Hubbard Andrew , Bombardier Eric , Tiidus Peter 
Published: June 2021

17β‐Estradiol (E2) enhances activation, proliferation and differentiation of muscle satellite cells (SCs) following exercise via activation of estrogen receptor‐α (ER) and phosphatidylinositol 3‐kinase (PI3K) signaling. Supplementation of E2 through hormone replacement has been shown to ameliorate muscle atrophic effects of menopause in women. Delay in post‐menopause E2 replacement in humans or following ovariectomy in rodents has resulted in negation of positive health or regenerative effects of E2 on various tissues. To determine if delay in E2 replacement influenced E2 effects on skeletal muscle, 64, nine‐week old, ovariectomized Sprague‐Dawley rats were divided into eight groups based on: E2 status (0.25 mg estrogen pellet or sham), exercise status (90 min run @ 17 m/min, ‐13.5° or unexercised) and E2 replacement (“proximal”; E2 replacement within one week or “delayed”; eleven‐weeks following ovariectomy). Significant increases in total SCs were found in soleus muscle (immunofluorescent co‐localization of nuclei with Pax7) 72 hr following eccentric exercise (p < 0.05). Only “proximal” estrogen‐replacement resulted in further enhancement in total muscle SCs in exercised rats (p < 0.05). Delayed estrogen‐supplementation did not produce a further augmentation in post‐exercise SCs. This suggests the existence of a short window of opportunity where E2 replacement must commence following loss of endogenous estrogen production in order for benefits to skeletal muscle regeneration to manifest.Grant Funding Source: Supported by NSERC
Muscle protein synthesis, degradation and the effect of mTORC1, after resistance exercise (1163.7)
Authors: West Daniel , Baehr Leslie , Shamim Baubak , Gomes Aldrin , Bodine Sue , Baar Keith 
Published: June 2021

We aimed to measure mTORC1 signaling, rates of muscle protein synthesis (MPS), and proteasome activity after acute resistance exercise (REx). A second aim was to determine whether mTORC1 signaling impacted MPS in late recovery. Rats (8 m.o. FBN hybrids) underwent unilateral hindlimb stimulation that eccentrically contracted the tibialis anterior (TA). All measures in the stimulated TA were expressed relative to the contralateral control TA. TA muscles were collected at 1.5, 3, 6, 18, and 36 h after REx, and at 3 and 18 h after REx plus rapamycin treatment to block mTORC1 activity. There was a robust activation of mTORC1, whereby phosphorylation of S6K1 (T389) peaked at 3 h (134±22‐fold inc.) and returned to baseline by 18 h; phosphorylation of S6 (S240/244) peaked at 6 h (26±4‐fold inc.). MPS peaked at 6 h (67±31% inc.) before gradually declining toward baseline through 36 h. Principal proteasome activities, 26S and 20S beta5, tended to decrease (~15‐20% at 6‐12 h), and then increase at later time points (~15‐20% above rest at 18‐36 h). Interestingly, rapamycin treatment, while completely blocking increases in p‐S6K1, only partially blocked the elevation in MPS at 18 h. In summary, REx stimulated a large increase in mTORC1 signaling and a moderate sustained increase in MPS, and inhibiting mTORC1 did not fully abolish the MPS effect at 18 h. Further, for the first time, we have directly measured proteasome activity after REx.Grant Funding Source: Supported by NSERC and Veteran Affairs (RR&D Merit Grant E7766‐R)
Extracellular ATP as a relevant mediator between skeletal muscle depolarizaition and interleukin‐6 expression: from cell culture to whole animal adaptations (1164.10)
Authors: Buvinic Sonja , Bustamante Mario , Fernández‐Verdejo Rodrigo , Casas Mariana , Vásquez Javiera , Jaimovich Enrique 
Published: June 2021

Interleukin‐6 (IL6) is a relevant myokine, highly expressed in skeletal muscle cells upon exercise. We have demonstrated that extracellular ATP is a relevant mediator between skeletal muscle depolarization and intracellular calcium signaling leading to gene expression. The aim of this work was analyze the role of this pathway in controlling IL6 expression, from culture cells to an animal model.In the L6 skeletal cell line overexpressing Pannexin 1, leading to a rise in ATP release at rest, IL6 expression was 2.5 fold increased. In newborn‐derived rat myotubes, IL6 expression evoked by a tetanic electrical stimulation was abolished when extracellular ATP signaling was blocked by the ectonucleotidase apyrase or by the P2Y/P2X receptors general inhibitor suramin. In myotubes and isolated mice skeletal fibers, both exogenous ATP and ADP increased IL6 expression in a concentration dependent manner. In myotubes, ATP evoked IL6 expression through a pathway involving Ca2+ and IL6 release, activating an autocrine positive loop. In a physiological model of exercise, skeletal fibers from voluntarily active mice (5 weeks voluntarily training in an exercise wheel) had an increased sensitivity to ATP for IL6 expression compared with sedentary mice; ATP sensitivity directly depended on the level of physical activity performed. Considering that increased ATP sensitivity occurs even in the absence of metabolic modifications, ATP sensitivity emerges as an early, highly sensitive marker of muscle adaptation to training. This could have an impact not only in the exercise‐dependent expression of IL‐6 but also in other physiopathological responses.Grant Funding Source: Supported by Fondecyt‐1110467‐11100454, Conicyt‐79090021, FONDAP‐15010006, ACT‐1111
Influence of sympathetic vasoconstriction on muscle blood flow control during graded handgrip exercise in young and older adults (1165.2)
Authors: Richards Jennifer , Crecelius Anne , Hearon Christoper , Racine Matthew , Larson Dennis , Luckasen Gary , Dinenno Frank 
Published: June 2021

With human aging there is a marked increase in resting sympathetic nervous system (SNS) activity, and older adults also exhibit attenuated vasodilation and skeletal muscle blood flow during exercise.We tested the hypothesis that SNS restraint of muscle (forearm) blood flow (FBF) is greater in older compared with young adults during graded handgrip exercise (5, 15, 25% maximal voluntary contraction (MVC)). FBF was measured (Doppler ultrasound) and vascular conductance (FVC) was calculated in 12 young (21±1 years) and 12 older (62±2 years) adults in control conditions and following local α+β‐adrenergic receptor blockade (intra‐arterial infusions of phentolamine and propranolol). Compared to young, older adults exhibited significantly lower FBF at 15% MVC (216±12 vs. 177±15 ml/min) and 25% MVC (344±24 vs. 277±17 ml/min; both P<0.05). Following local adrenergic blockade, the increase in FBF was similar in young and older adults across exercise intensities, and the age difference in FBF during exercise was similar to control conditions. Our data indicate that, during graded mild‐to‐moderate intensity handgrip exercise, the reduction in muscle blood flow in older healthy adults is not due to augmented sympathetic vasoconstriction, but rather due to impairments in local vasodilatory signaling with age.Supported by HL095573Grant Funding Source: Supported by HL095573
Increased brain‐derived neurotrophic factor in lumbar dorsal root ganglia contributes to the exaggerated exercise pressor reflex in heart failure (1165.7)
Authors: Wang Hanjun , Wang Wei , Rozanski George , Zucker Irving 
Published: June 2021

An exaggerated exercise pressor reflex (EPR) causes excessive sympatho‐excitation and exercise intolerance during physical activity in the chronic heart failure (CHF) state. Evidence showed that the peripheral sensitization of muscle mechanical afferents (mechanoreflex) is an important contributor to the exaggerated EPR in CHF whereas the metaboreflex is blunted. To date, the mechanisms underlying the selective sensitization of the mechanoreflex in CHF remain unclear. We hypothesized that brain‐derived neurotrophic factor (BDNF) in muscle afferent neurons plays a critical role in the sensitization of the mechanoreflex in CHF. Increased BDNF expression was observed in lumbar DRGs from CHF rats compared to sham rats (8.3±1.1 vs. 19.5±1.8 pg/g, n=6, P<0.05). Immunofluorescence further showed a greater increase in the number of BDNF‐positive neurons (mainly mechanically sensitive, marked by NF200) in CHF rats. Finally, chronic epidural delivery of anti‐BDNF (10 µg/ml) to the lumbar DRGs attenuated the exaggerated pressor response to either static contraction (EPR activation) or passive stretch (mechanoreflex) in CHF rats whereas this intervention had no effect on the pressor response to hindlimb arterial injection of capsaicin (metaboreflex activation). These data suggest that increased BDNF in lumbar DRGs contributes to the exaggerated EPR by sensitizing the mechanoreflex in CHF rats.Grant Funding Source: American Heart Association (#12SDG12040062)
Acute hypoxia rapidly alters myotube size in vitro and myostatin signalling in vivo (1167.1)
Authors: Elliott Bradley , Renshaw Derek , Getting Stephen , Watt Peter , MacKenzie Richard 
Published: June 2021

Skeletal muscle loss correlates with mortality across chronic pathological disorders. Chronic O2 reduction induces atrophy in healthy mountaineers and hypoxemic COPD patients. Hypoxic rats and hypoxemic COPD patients show elevated myostatin expression, a regulator of muscle protein turnover and satellite cell proliferation. We hypothesized hypoxia induces atrophy via myostatin signalling.C2C12 myoblasts (N = 3) were scratched and exposed to 18 hrs of 21% or 1% O2 +/‐ 10 µM PS145 (NF‐κB inhibitor) to measure migration. Myotubes (N = 3) were exposed to 2, 24 or 48 hr of 21% or 1% O2 +/‐ 10 µM PS145 to measure atrophy. Healthy males (N = 9) were exposed to 12% O2 for 2 hours with muscle tissue and plasma collected pre‐ and post‐exposure. Protein expression was quantified by Western blot (muscle) or ELISA (plasma).Hypoxic myoblasts showed reduced migration. Hypoxic myotubes showed atrophy at 2 hr, which increased at 24 and 48 hr. Hypoxic impairment of myoblast migration and myotube atrophy was offset by PS1145 incubation. Hypoxic participants showed reduced muscle myostatin, and trends for increased ubiquitin binding and NF‐κB activity. Plasma myostatin was unchanged.Here we demonstrate hypoxia rapidly induces atrophy in vitro via NF‐κB dependent mechanisms. Hypoxia alone induces atrophy, independent of other factors, and an atrophic environment in vivo similar to that seen in chronic hypoxic disorders, such as COPD.Grant Funding Source: Supported by The Society for Endocrinology (UK)
Muscle adaptation in obese rats exposed to chronic hypoxia (1167.3)
Authors: Gamboa Jorge , Macarlupu Jose , Anza Cecilia , Rojas Percy , Villafuerte Francisco 
Published: June 2021

Chronic hypoxia decreases fasting glucose and increases glucose utilization in lean and obese rats. Hypoxia increases insulin sensitivity in obese rats, but insulin resistance remains higher compared to lean rats exposed to hypoxia (figure). Skeletal muscle plays an important role in glucose metabolism; thus changes in insulin pathway and mitochondrial metabolism may impact skeletal muscle glucose uptake. We evaluated the adaptation of skeletal muscle to chronic hypoxia in lean and obese rats. We hypothesized that obese rats have less mitochondrial protein content and decreased activation of the ERK/MAPK pathway, one of the components of the insulin‐signaling cascade. For this purpose, Sprague‐Dawley rats were fed with normal chow diet or high‐fat diet (45% Kcal from fat) for 24 weeks in a normoxic environment. Rats were then exposed to hypobaric hypoxia (simulated altitude of 4500m) for 3 weeks. Triceps surae muscles were removed at the end of the hypoxia exposure and processed for western blot analysis. Mitochondrial protein content was evaluated using a monoclonal antibody against the subunit α of complex V. Contrary to our hypothesis, obese rats have a higher mitochondrial protein content than lean rats (35% higher, p=0.025). There was no difference in the activation of the ERK/MAPK pathway between the groups. Further studies are required to elucidate how chronic hypoxia affects glucose metabolism in obese rats.$graphic_082DEB25‐E5FC‐41C5‐820C‐9A23528E6536$Grant Funding Source: Supported by FINCyT (No 046‐FINCyT‐PITEI‐2010) and NIH (K23DK100533)