bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise and Isoproterenol‐Induced Cardiac Hypertrophy in Aged Mice
Authors: Luckey Stephen , McLaughlin Nathan , Soo Sherilynn 
Published: November 2023

Approximately half of the people with heart failure are older than 75 year of age. Despite this statistic, and the fact that the aged heart undergoes changes that impact its structure and function, the vast majority of heart failure research is conducted using young animal models. Therefore, the objective of this study was to investigate how age‐related changes affect the ability of the heart to adapt to physiological (e.g. exercise) and pathological (e.g. heart failure induced by beta adrenergic stimulation) stimuli. CB6F1 male mice at 22 months of age were used for this investigation. Mice were divided into four groups: sedentary, voluntary exercise, vehicle, and isoproterenol. We assessed exercise capacity and found that these mice voluntarily ran on a cage wheel and, on average, ran 2.4 ± 0.3 km and spent 2.9 ± 0.4 hours per day on the wheel. Wheel running speed was 0.8 ± 0.1 km/hr when averaged over the 3‐week period. Although mice had a slight, but insignificant increase in heart weight‐to‐tibial length ratio (HW/TL), exercise induced a 13% increase in left ventricle‐to‐tibial length ratio (LV/TL). Mini‐osmotic pumps delivered vehicle or isoproterenol (30mg/kg/day) for 14 days. Isoproterenol treatment resulted in a 10% and 13% increase in HW/TL ratio and LV/TL ratio, respectively. In conclusion, these investigations suggest that the aged left ventricle has the ability to undergo cardiac hypertrophy following physiological or pathological stimuli. We are currently investigating the underlying molecular and cellular mechanisms that play a role in the observed cardiac adaptations.Support or Funding InformationM.J. Murdock Charitable Trust (S.W.L.)
Myocardial Glycolytic Rate Regulates Exercise‐Induced Physiologic Cardiac Growth
Authors: Gibb Andrew , Gilbert Lindsey A , Brittian Kenneth R , Jones Steven P , Bhatnagar Aruni , Hill Bradford G 
Published: November 2023

BACKGROUNDRegular exercise improves quality of life and decreases all‐cause mortality, in part due to improvements in cardiovascular health. Repetitive exercise enhances cardiac function by promoting cardiomyocyte growth and increasing angiogenesis, and is associated with elevated myocardial glucose and fatty acid utilization. Nevertheless, it is unclear whether changes in myocardial metabolism are causative in cardiac adaptations to exercise. In this study, we tested the hypothesis that exercise‐induced increases in myocardial glycolysis are required for physiological cardiac growth.METHODSFifteen week‐old, male FVB/NJ transgenic (Tg) mice expressing a cardiac‐specific, dominant‐negative form of phosphofructokinase 2, which decreases myocardial glycolytic rate, and their wild‐type (WT) counterparts were subjected to sedentary (SED) conditions or forced treadmill exercise (EXE) for 30 days. Systemic and cardiac‐specific adaptations to exercise were assessed by measuring exercise capacity and echocardiographic changes in cardiac structure and function; biochemical signatures of adaptation were measured by immunohistochemistry, qPCR and immunoblotting.RESULTSIn WT mice, exercise training increased distance run by 42% (p<0.0001) and work performed by 69% (p<0.0001). Exercise promoted cardiac growth (heart‐to‐tibia length: SED, 6.7±0.2 mg/mm vs. EXE, 7.7±0.4 mg/mm; p<0.0001), which was due to myocyte hypertrophy (myocyte cross‐sectional area: SED, 461±43 μm2 vs. EXE, 564±40 μm2; p<0.01). Exercise capacity was not different between WT and Tg mice; however, unlike WT EXE mice, which showed increased end diastolic volume, stroke volume, and cardiac output after exercise (p<0.05), exercise did not change these indices of cardiac function in Tg mice. Interestingly, the Tg SED and EXE mice displayed a hypertrophic heart, characterized by elevated atrial natriuretic peptide (p<0.01), indicating activation of a fetal gene program. Moreover, unlike WT mice, Tg mice failed to show exercise‐induced activation of Akt, which is necessary for physiological cardiac growth and adpatation, and demonstrated lower expression of the pro‐angiogenic factor, VEGF.CONCLUSIONSDiminished cardiac glycolytic rate prevents cardiac adaptations to exercise and may act as a pivotal regulator of physiological and pathological hypertrophic programs.Support or Funding InformationACKNOWLEDGEMENTS: This work was funded by the NIH (GM103492 and HL122580).
Satellite Cell Behavior in Cyclists Following Intensified Training With and Without Protein Supplementation
Authors: Luden Nicholas , McKenzie Alec , Saunders Michael , Womack Christopher , D'Lugos Andrew , Gworek Keith 
Published: November 2023

Our objective was to investigate the satellite cell (SC) response of endurance‐trained cyclists (n=8) to 10 days of intensified cycle training (ICT) and 10 days of subsequent recovery (RVT – reduced volume training), with carbohydrate (CHO) and carbohydrate‐protein (PRO) supplementation. Muscle biopsies were obtained from the vastus lateralis before and after ICT and RVT. Immunofluorescent microscopy was used to analyze SCs and myosin heavy chain (MHC) I and IIa. Data were analyzed using magnitude‐based inferences. MHC I SCs were abundant at baseline (38 ± 20 SCs/100 fibers), decreased (unclear) from PRECHO to ICTCHO, and then likely increased by 60 ± 64% following RVTCHO. No other changes in SC content were observed. Myonuclear content of MHC I fibers most likely increased (16 ± 6%) from baseline to ICTCHO. Likewise, MHC IIa myonuclear content likely increased (14 ± 14%) from PRECHO to RVTCHO. Though there were no changes in fiber size (cross sectional area) under CHO conditions, ICT with PRO supplementation very likely increased MHC I size (14 ± 8%) and likely increased MHC IIa size (16 ± 19%). Trained endurance cyclists possess a relatively large pool of SCs that appeared to facilitate myonuclear accretion with heavy training under carbohydrate conditions. These data strengthen the growing body of evidence demonstrating the non‐hypertrophic role of SCs in skeletal muscle and the possible benefit of protein supplementation.Support or Funding InformationThis project was supported by James Madison University's College of Health and Behavioral Studies Faculty Research Grant (N. Luden and A. McKenzie) and the Dairy Research Institute (N. Luden and M. Saunders).
Combined Exercise Training Promotes Additional Benefits Than Aerobic or Resistance Training in a Model of Metabolic Syndrome and Menopause
Authors: Conti Filipe F , Brito Janaina O , Dias Danielle S , Bernardes Nathalia , Malfitano Christiane , Irigoyen Maria‐Claudia , De Angelis Kátia 
Published: November 2023

The aim of this study was to verify the effects of three different moderate exercise training protocols (aerobic, resistance and combined (aerobic + resistance)) in a model of metabolic syndrome and menopause on a cardiovascular parameter and oxidative stress. Female SHR rats were divided into (n=8): hypertensive (H), hypertensive ovariectomized submitted to fructose overload (100g/L in drinking water) (HFO), aerobic trained hypertensive ovariectomized submitted to fructose overload (AHOF), resistance trained hypertensive ovariectomized submitted to fructose overload (RHOF) and combined trained hypertensive ovariectomized submitted to fructose overload (CHOF). Arterial pressure (AP) signals were directly recorded. Vascular autonomic modulation was evaluated by spectral analysis. The cardiac oxidative stress was evaluated by chemiluminescence (CL) determination. The association of fructose overload and hormone deprivation promoted an increase in AP (HOF: 174±4 vs. H: 146±4 mmHg), heart rate (HOF: 393±10 vs. H: 352±13 bpm), LF‐SAP (HOF: 10.6±2.3vs. H: 5.0±0.9 mmHg2) and CL. On the other hand, all exercise training protocols were able to reduce the CL and LF‐SAP. It was noted that only the combined exercise training reduced the AP (CHOF: 158±4 mmHg) and the heart rate (CHOF: 303±5 bpm). In all, fructose overload induced impairment in hemodynamic, vascular autonomic control and increased oxidative stress in hypertensive rats submitted to ovarian hormones deprivation. However, all exercise training protocols showed a beneficial role. Moreover, the combined exercise training showed additional improvement, suggesting that this could be a better approach than isolated aerobic and resistance training.Support or Funding InformationFAPESP ‐2011/15828‐9; 2010/17188‐4; 2012/20141‐5 CNPq ‐ 479766/2011‐8
Reversing the effects of chronic stress on the aorta with exercise training
Authors: Lemaster Kent , DeVallance Evan , Branyan Kayla , Skinner Roy , Brooks Steve , Asano Shinichi , Killmer Cameron , Olfert Mark , Bryner Randall , Frisbee Jefferson , Chantler Paul 
Published: November 2023

Individuals with increased levels of chronic stress have an increased aortic stiffness which is a strong, independent risk factor for cardiovascular disease. Additionally, chronic stress is associated with a decreased capacity for endothelium‐dependent, nitric oxide (NO)‐induced vasorelaxation which may contribute to the aortic stiffness and increased after load on the heart. Using the unpredictable chronic mild stress protocol (UCMS), lean zucker rats (LZR; healthy rats) develop impaired vascular reactivity in aortic rings concomitant to the onset of chronic stress pathologies. Therapeutic interventions aimed at improving endothelial functioning are therefore considered important avenues for improving CV outcomes in stressed patients. We hypothesized that a chronic aerobic exercise intervention would improve endothelium‐dependent relaxation to methacholine in isolated aortic rings of stressed LZRs. A total of 22 LZRs underwent 8 weeks of a treadmill exercise protocol beginning at 9 weeks of age. The animals were separated into 4 groups: sedentary LZR (LZR; n=7); UCMS LZR (UCMS‐LZR; n=8); exercise and UCMS (ExUCMS‐LZR n=7). Following the intervention, the thoracic aorta was dissected out from each animal and sectioned into rings, some of which were then mounted into an ex vivo wire tension myograph system. The remaining rings were evaluated for NO production in a DAF‐FM diacetate assay. Force transduction was used to measure the changes in aortic tension in response to pharmacological agonists. The aortic rings were mechanically set to 1 gram of tension then pre‐constricted using phenylephrine (1×10‐6μM), followed by a gradual dilation induced by increasing concentrations of methacholine (1×10‐9, 1×10‐8, 1×10‐7, 1×106, 1×10‐5 μM respectively). The LZR group demonstrated greater methacholine‐induced maximal vasorelaxation compared to the UCMS‐LZR group (83% vs. 78%). The ExUCMS‐LZR group experienced the greatest maximal dilation (90%) as well as increased values of NO production measured in the DAF assay compared to LZR group and UCMS‐LZR group. These results demonstrate that 8 weeks of aerobic exercise enhances endothelial bioavailability and/or production of NO which improves endothelium‐dependent vasorelaxation in the aortas of stressed LZRs even more so than the sedentary control. Exercise training may therefore be an important therapy for promoting greater arterial compliance of chronically stressed individuals.Support or Funding InformationNIHAHA
Hemodynamic responses to cooling and warming during a continuous simulated hemorrhage ramp
Authors: Poh Paula Y. S. , Gagnon Daniel , Romero Steven A. , Convertino Victor A. , Crandall Craig G. 
Published: November 2023

One in 10 deaths worldwide is caused by traumatic injury, and 30–40% of those trauma‐related deaths are due to hemorrhage. Currently, warming a hemorrhaging victim is the standard of care due to the adverse effects of combined hemorrhage and hypothermia on survival. However, heating can be detrimental to the maintenance of arterial pressure and cerebral perfusion during a continuous hypotensive challenge.PURPOSETo test the hypothesis that warming a normothermic individual during a continuous simulated hemorrhage ramp is harmful to the maintenance of arterial pressure and cerebral perfusion, while skin surface cooling is beneficial.METHODSTwelve men (mean ± SD: age, 29 ± 8 y; weight, 82 ± 16 kg) underwent a randomized crossover study performed over 3 separate days. Following 15 min of supine rest, 10 min of 30 mmHg of lower body negative pressure (LBNP) was applied to simulate a mild hemorrhagic challenge. With LBNP continuing, subjects were then exposed to mild whole‐body warming (WARM; mean skin temperature (Tsk): 36.4 ± 0.5°C), skin surface cooling (COOL; Tsk: 30.5 ± 0.9°C), or remained thermoneutral (NEUT; Tsk: 33.9 ± 0.6°C). Five min after the thermal provocation, a continuous LBNP ramp was applied at a rate of 5 mmHg·min−1 until pre‐syncope. Hemodynamic and thermal variables were measured continuously.RESULTSNeither average time to pre‐syncope (P = 0.14) nor the LBNP level at pre‐syncope (P = 0.09) were different between thermal conditions. However, mean arterial blood pressure was elevated (92 ± 11 mmHg; P = 0.01) during COOL across the LBNP period, relative to NEUT (83 ± 9 mmHg) and WARM (79 ± 11 mmHg) trials. Middle cerebral artery blood velocity decreased (26 ± 1 cm·sec−1; P < 0.001) to a similar extent from baseline to pre‐syncope, regardless of the thermal conditions applied.CONCLUSIONSContrary to our hypothesis, WARM did not impair LBNP tolerance or cerebral blood flow velocity. Although COOL increased blood pressure during the LBNP ramp, LBNP tolerance and cerebral perfusion were not different relative to the NEUT or WARM trials. These data indicate that mild whole‐body warming of a continuously hemorrhaging victim is not detrimental to hemodynamic stability.Support or Funding InformationProject funded by DOD‐W81XWH‐12‐1‐0152.
Contribution of Satellite Cells to Skeletal Muscle Proteostasis during Advanced Age and Aerobic Exercise
Authors: Konopka Adam R. , Ehrlicher Sarah E. , Baeverstad Kathryn A. , Reid Justin , Peelor Fredrick F. , Confides Amy L. , Dupont‐Versteegden Esther E. , Miller Benjamin F. , Hamilton Karyn L. 
Published: November 2023

We have shown that the maintenance of skeletal muscle proteostasis is a shared characteristic in several animal models of slowed aging. Loss of satellite cell activity with advancing age has been correlated to impaired skeletal muscle remodeling however emerging evidence suggests satellite cells may not be requisite in preventing age‐related changes in skeletal muscle. It remains to be determined how satellite cell recruitment influences protein turnover during advanced age and after exercise. We hypothesized that satellite cells will have a minimal contribution to skeletal muscle proteostasis during aging and exercise. To test this hypothesis, at 4 months of age Pax7CreER‐DTA mice were treated with vehicle or tamoxifen to deplete satellite cells. The gastrocnemius muscle was harvested from young (7–10 months old) and old (23–24 months old) mice. A subset of mice from both age and treatment groups had access to voluntary running wheels (exercised) for the last two months to provide a stimulus for satellite cell recruitment while the other mice remained ambulatory (non‐exercised). After an intial i.p. bolus, mice received 8% D2O in their drinking water during the last 6 weeks of each intervention to assess the integrated synthesis rates of skeletal muscle subcellular fractions and DNA. Skeletal muscle mitochondrial and collagen protein synthesis were lower in aged mice regardless of satellite cell content, which is consistent with the notion of age‐related impairments in mitochondrial biogenesis and extracellular matrix turnover. Compared to vehicle, tamoxifen treatment decreased mitochondrial and collagen synthesis in the young, non‐exercised group. Collagen synthesis remained lower in aged, exercised mice with no influence from satellite cells. Interestingly, when satellite cells were depleted, mitochondrial protein synthesis was elevated in the exercised group. Additional analysis regarding DNA synthesis is forthcoming and warranted to provide context for the novel relationship between satellite cell depletion and augmented mitochondrial biogenesis after exercise. Although the mechanisms linking satellite cell depletion to augmented mitochondrial biogenesis after exercise remain unknown, these data suggest in the absence of satellite cells the energetic stress of exercise may selectively increase mitochondrial protein synthesis. These findings are consistent with our previous studies that indicate energetic stress favors cellular resources to be allocated for maintaining existing cellular structures rather than cell proliferation.Support or Funding InformationNIA Grants AG043721 to EEVD and AG042569 to BFM and KLH.
Chronic Binge Alcohol (CBA) Administration decreases miR‐206 in simian immunodeficiency virus (SIV)‐infected Macaques
Authors: Simon Liz , Molina Patricia E 
Published: November 2023

Decreased skeletal muscle (SKM) mass and function remains a strong and consistent predictor of mortality among persons living with HIV/AIDS (PLWHA) and occurs at an earlier age among PLWHA compared to the general population. SKM dysfunction is also prevalent in individuals with alcohol use disorders (AUDs). Previously we showed that CBA accentuates SKM wasting in simian immunodeficiency virus (SIV) infected rhesus macaques and this is associated with enhanced myoinflammation, oxidative stress, ubiquitin proteasome proteolytic pathways, and decreased regenerative capacity of SKM progenitor cells. This study tested the hypothesis that CBA‐induced alterations in SKM microRNA (myomiR) expression may contributing to impaired SKM regeneration in SIV‐infected macaques. Daily CBA (blood alcohol levels ~50 mM) or sucrose (SUC) administration was initiated 3 months prior to intrarectal SIVmac251 inoculation and continued throughout the study period. Antiretroviral therapy (ART) or placebo was initiated 2.5 months after SIV infection and continued through the study period. Four treatment groups (SUC/SIV±ART and CBA/SIV±ART) were studied at endpoint (11 months post SIV inoculation). Primary myoblasts isolated from SKM samples from CBA/SIV/ART+/− showed decreased myotube formation, myonuclei fusion index, and myogenic gene expression compared to those derived from SUC/SIV macaques. This was associated with decreased SKM miR‐206 expression. Transfection of naïve macaque myoblasts with a miR‐206 inhibitor resulted in a significant decrease in myogenic enhancer factor 2C (MEF2C), and decreased differentiation of myoblasts, suggesting a critical role of miR‐206 in myogenesis in macaque myoblasts. Circulating plasma levels of miR‐206 were significantly decreased in CBA/SIV/ART+/− macaques, reflecting a similar pattern to that seen in SKM. These results suggest altered SKM myomiR expression as a likely mechanism for decreased regenerative capacity in SKM of CBA/SIV macaques, irrespective of ART. The parallel changes in SKM and circulating levels of miR‐206 suggest the possible use of plasma miR‐206 as an indicator of impaired regenerative capacity in SKM of PLWHA and is currently under investigation.Support or Funding InformationThe work was supported by National Institutes of Health (NIH) grants: P60 AA09803
Sarcolemma Wounding Activates Dynamin Dependent Endocytosis in Striated Muscle
Authors: Thorson Molly T. , McDade Joel R. , Michele Daniel E. 
Published: November 2023

RationaleMutations in the protein dysferlin have been shown to result in Limb Girdle Muscular Dystrophy 2B and Myoshi Myopathy. In patients and mouse models lacking dysferlin, dysfunctional membrane repair compromises the muscle cells and leads to muscle degeneration and progressive muscle wasting. Preliminary data in our laboratory suggests that sarcolemmal wounding stimulates the endocytosis of dysferlin. Therefore, the objective of this study was to investigate the potential regulators of wound‐induced membrane transport. We hypothesized that the activity of dynamin, a GTPase that facilitates endocytosis, may be important for the activation of membrane trafficking following wounding and possibly important for the wound‐induced endocytosis of dysferlin.Methods and ResultsMuch research in the field has focused on measuring membrane disruption by monitoring the uptake of the extracellular, lipophilic dye, FM1‐43. However, FM1‐43 can also be used as a measure of endocytosis. Therefore, we used FM1‐43 dye to track endocytosis in adult skeletal muscle fibers at rest and following acute sarcolemma disruption. We show that while dysferlin recruitment to the wound site is not dependent upon dynamin, initial FM1‐43 loading is completely dependent upon dynamin activity. Furthermore, dynamin inhibition significantly reduces wound‐induced FM1‐43 uptake, suggesting that wound‐induced uptake occurs via dynamin‐dependent endocytosis. We show, in agreement with others, that dysferlin‐deficient muscle fibers show elevated FM1‐43 uptake following wounding, which is the basis for the assertion that membrane repair is defective in this model. However, our data suggest that the upregulation of wound‐induced endocytosis may contribute to the increased uptake of FM1‐43 following wounding in dysferlin‐deficient muscle fibers.ConclusionsThese data highlight a previously unappreciated role for dynamin‐dependent endocytosis in resting and wounded adult skeletal muscle fibers. Importantly, FM1‐43 uptake following wounding is considered to be the “gold standard” for membrane repair studies in muscle. However, these data also suggest FM1‐43 uptake following wounding may reflect wound‐induced endocytosis, in addition to local influx of dye at the wound. Research in our laboratory is exploring the use of other methods of measuring membrane repair in order to distinguish the process of wound‐induced endocytosis from local re‐sealing of the wound site itself.Support or Funding InformationThis work has been supported by the American Heart Association (#12PRE12050130) to JM, the NIH Cellular and Molecular Biology Training Grant T‐32‐GM007315 to MT and NIH NIAMS AR066213 to DM.
Effects of PGC‐1α Overexpression on Glucocorticoid‐induced Atrophy Signaling in C2C12 Muscle Cells
Authors: Rahnert Jill A , Perry Ben D , Zheng Bin D , Price Russ 
Published: November 2023

Muscle wasting (atrophy) is a debilitating consequence of many catabolic conditions and has been linked to decreased expression of the transcriptional coactivator PGC‐1α. In some models of atrophy, overexpression of PGC‐1α attenuates muscle loss, in part, by reducing FoxO‐mediated atrophy gene expression. FoxOs are transcription factors regulated primarily by phosphorylation via Akt. Previous studies indicate that activation of Akt prevents downstream FoxO signaling during atrophy and that overexpression of PGC‐1α increases phosphorylation (i.e. inhibition) of FoxO proteins. The goal of this study was to determine whether increasing PGC‐1α protein preserves Akt phosphorylation using two in vitro models of atrophy, starvation and glucocorticoid treatment. C2C12 myotubes were infected with an adenovirus encoding GFP (control) or PGC‐1α followed by incubation in control differentiation media (DMEM + 2% horse serum), serum‐free DMEM (SF) to induce starvation, or differentiation media with the synthetic glucocorticoid, dexamethasone (Dex, 1uM), for 24h. Infection of cells with the PGC‐1α adenovirus increased PGC‐1α mRNA and protein and augmented Akt phosphorylation. In GFP‐expressing myotubes, SF reduced PGC‐1α protein and Akt phosphorylation and overexpression of PGC‐1α attenuated the starvation response. Dex did not alter PGC‐1α protein or Akt phosphorylation, however, it increased the FoxO target gene, Atrogin‐1. In addition, overexpression of PGC‐1α increased PGC‐1α protein in Dex‐treated cells and attenuated the increase in Atrogin‐1. These data suggest that maintenance of Akt phosphorylation may contribute to the protective effect of PGC‐1α. Furthermore, they underscore the role of PGC‐1α in the preservation of muscle protein during glucocorticoid‐mediated atrophy.Support or Funding InformationSupported by NIH RO1 DK95610, NIH T32 DK007656 and VA Merit I01BX001456