bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing Atrophy‐Inducing Signals on ER Stress in C1 C1 2 Muscle Cells
Authors: Newberry Erin R , Rahnert Jill A. , Price Russ 
Published: November 2023

Muscle wasting (atrophy) is a consequence of chronic diseases, such as kidney disease or diabetes, and reduces the patient's overall quality of life and functional independence. Previous studies in this lab show that muscle cells treated with palmitate (Palm, a saturated fatty acid) activates ER stress and contributes to the atrophy process. The purpose of our experiments is to determine whether ER stress is a common feature of atrophy signaling by comparing the effects of two known inducers of muscle atrophy, glucocorticoids and Palm, on ER stress markers. Glucocorticoids are elevated during physiological stress like chronic diseases and are permissive for muscle wasting. Therefore, we tested the hypothesis that glucocorticoids increase markers of ER stress. C1 C1 2 muscle cells were treated with 1μM Dexamethasone (DEX, a glucocorticoid) and/or 500μM of Palm. The mRNA levels of the ER stress markers ATF4 and CHOP were measured by qPCR methods. ATF4 represents one of three arms of the ER stress response and CHOP represents an integrated response of all three arms. Treating myotubes with DEX had little effect on ATF4 or CHOP mRNA levels compared to the control. Palm did not change ATF4 mRNA but, similar to previous work, Palm increased CHOP mRNA. Co‐treatment of Palm and Dex synergistically increased both ATF4 and CHOP. These results suggest that in the presence of other atrophy signals, glucocorticoids act synergistically to enhance ER stress signaling. Future studies will evaluate whether activation of ER stress in co‐treated cells prolongs cell survival.Support or Funding InformationR25DK101390, VA‐MERIT I01BX001456, NIH R01 DK 95610, NIH T32 DK 007656
IL‐33 Receptor Gene Deletion and Skeletal Muscle Abnormalities in a Mouse Model of Pulmonary Arterial Hypertension
Authors: Cannon Daniel T , Gutierrez Alma , Tsui Tzuhan , Lerner Andrew D , Breen Ellen C , Bigby Timothy D 
Published: November 2023

Pulmonary arterial hypertension (PAH) is a progressive, incurable disease of the pulmonary vasculature, leading to high pulmonary vascular resistance and right ventricular failure. In addition, PAH patients show marked skeletal muscle abnormalities that may develop before right heart pathology. Thus, skeletal muscle dysfunction may be more closely related to the primary pathology of PAH than originally thought. We hypothesized that IL‐33, recently implicated in the cardiopulmonary pathogenesis of PAH, is also requisite for skeletal muscle maladaptation.Using adult C57BL/6J mice, we induced PAH with 3 wks of chronic hypoxia (FiO2 0.10) and weekly subcutaneous injections (20 mg.kg−1) of the VEGF receptor kinase inhibitor Su5416 (SuHx). SuHx was applied in both wild‐type (WT) and IL‐33 receptor gene ablated (ST2−/−) mice. Further, vehicle control (DMSO) WT mice were generated using the same injection volume and schedule and were housed in normoxia (CON). Mitochondrial function was measured in permeabilized diaphragm and soleus using a titration protocol that included maximal ADP‐stimulated respiration (JO2max) and non‐phosphorylating electron transport system capacity (ETS).Diaphragm JO2max was reduced in WT‐SuHx vs. WT‐CON (85±26 vs 162±62 pmol.s.mg‐−1; p<0.05), but not in ST2−/−‐SuHx (148±102 pmol.s.mg‐−1; p>0.72 vs WT‐CON). Diaphragm ETS followed a similar pattern in WT‐SuHx vs WT‐CON (90±29 vs 167±63 pmol.s.mg‐−1; p<0.05), and was not different in ST2−/−‐SuHx vs WT‐CON (152±104 pmol.s.mg‐−1; p>0.73). Flux control ratios (JO2max/ETS) were not different between groups (p>0.75). Soleus JO2max was reduced in both WT‐SuHx and ST2−/−‐SuHx vs WT‐CON (70±33 and 86±38 vs 140±40 pmol.s.mg‐−1; p<0.05). Soleus ETS was also reduced in WT‐SuHx and ST2−/−‐SuHx vs WT‐CON (68±24 and 86±38 vs 140±30 pmol.s.mg‐−1; p<0.05). Similar to diaphragm, soleus flux control ratios were not different between groups (p>0.73).The SuHx model showed a profound reduction in skeletal muscle mitochondrial oxidative capacity, suggestive of similar abnormalities to those reported in patients with PAH. As the flux control ratios were not different in SuHx, reduced mitochondrial volume‐density was a more likely mechanism, rather than a deficit in the quality of integrated function between electron transport and phosphorylation. Global gene deletion of the IL‐33 receptor (ST2) prevented diaphragm mitochondrial deficits in SuHx, but soleus muscle was less well‐protected. Our data strengthen the hypothesis that inflammatory cytokines, such as IL‐33, may play a critical role in skeletal muscle maladaptation to PAH.Support or Funding InformationThis research was supported by the US Department of Veterans Affairs.
Chronic Heat Preconditioning Enhances Skeletal Muscle Function during Hypoxia and Reoxygenation
Authors: Zuo Li , Roberts William J. , Pannell Benjamin K. 
Published: November 2023

Skeletal muscle that is exposed to hypoxia followed by reoxygenation (H/R) is susceptible to dysfunction and fatigue. However, the mechanisms that underlie skeletal muscle fatigue during H/R are not completely understood. The purpose of our study was to determine the role that chronic heat preconditioning (CHP) may play in protecting skeletal muscle against the deleterious effects of H/R. We hypothesized that CHP would mitigate skeletal muscle fatigue and attenuate ROS formation during H/R. During CHP treatment, C57BL/6 mice were housed in a heating chamber at 42°C for 30 minutes. Next, the mice were transferred to another chamber at room temperature for 30 minutes. This cycle was repeated 3 times per day, 5 days/week, for 2 weeks. Following CHP, mice were sacrificed and their diaphragms were removed for muscle function analysis. The muscle strips were electrically stimulated in a contraction chamber filled with Ringer's solution during H/R. Our data revealed that CHP significantly increased muscle function during hypoxia (31.5 ± 1.7% for treated vs. 13.1 ± 2.7% for control, p < 0.05; expressed as percent of the maximal force at the end of the contraction protocol) and also showed a trend to increase muscle fatigue resistance during reoxygenation. We monitored cellular levels of reactive oxygen species (ROS) via confocal microscopy by utilizing dihydrofluorescein diacetate (Hfluor‐DA), which is a fluorescent probe sensitive to intracellular ROS. Compared to the non‐treated group, CHP‐treated muscle strips demonstrated mitigated ROS fluorescence at the end of both hypoxia and reoxygenation periods, respectively (p < 0.05). Our results suggest that CHP may play a protective role against muscle fatigue and ROS formation during H/R in skeletal muscle.Support or Funding InformationSupported by OU General Fund G110
Electromechanical Delay and Peripheral Fatigue: Partitioning the Contributors during Electrically Evoked Contractions
Authors: Esposito Fabio , Monti Elena , Rampichini Susanna , Limonta Eloisa , Venturelli Massimo , Cè Emiliano 
Published: November 2023

Skeletal muscle contraction is a phenomenon involving several mechanisms that are electrochemical and mechanical in nature. The time lag between muscle electrical activation and the beginning of force production has been previously defined as the electromechanical delay. A novel electromyographic (EMG), mechanomyographic (MMG) and force (F) combined approach can provide the duration of the electrochemical and mechanical components of the total delay (DelayTOT). Prior investigations evaluated the acute effects of a fatiguing protocol on DelayTOT. The aim of this study was to evaluate the time course of the changes in the different DelayTOT components during a fatiguing stimulation. To this purpose, EMG, MMG and F signals were detected on the medial gastrocnemius muscle in eighteen male participants (age: 25±3 yrs; body mass: 77±4 kg; stature: 1.81±0.06 m; mean±SD) during a fatiguing protocol (twelve continuous stimulations at 35 Hz, 9.5 s on/0.5 s off; total time: 120 s) under isometric condition. Stimulation current (Stim) and EMG, MMG and F signals were recorded during contraction. The total electromechanical delay during contraction (DelayTOT) and its three components (between Stim and EMG: Δt Stim‐EMG, synaptic component; between EMG and MMG: Δt EMG‐MMG, electrochemical component; and between MMG and F: Δt MMG‐F, mechanical component) were calculated. Before fatigue DelayTOT was 22.3±0.9 ms. Δt Stim‐EMG, Δt EMG‐MMG and Δt MMG‐F relative contribution to DelayTOT was 6%, 48% and 46%, respectively. During fatigue, DelayTOT and Δt MMG‐F lengthened significantly in the first 40 s, then remaining stable, whereas Δt Stim‐EMG and Δt EMG‐MMG increased until the 10th and 30th s, respectively. At the end of the fatiguing protocol, F decreased by 44%. DelayTOT was 31.2±1.6 ms. Δt Stim‐EMG, Δt EMG‐MMG and Δt MMG‐F significantly changed their contribution to 5%, 43% and 53%, respectively. During a fatiguing stimulation, the present EMG, MMG and F combined approach unveiled a different effect of peripheral fatigue with time on the synaptic, electrochemical and mechanical components.Support or Funding InformationThe study has been funded by the Department of Biomedical Sciences for Health, University of Milan
The Molecular‐Clock and MyoD1 Work in a Synergistic Fashion to Promote Robust Circadian Expression of Titin‐cap in Skeletal Muscle
Authors: Hodge Brian Andrew , Zhang Xiping , Arnold Nick , Esser Karyn A 
Published: November 2023

Pressures caused by daily oscillations in the environment have favored the evolution of organisms that have adopted 24‐hour rhythmic cycles, or circadian rhythms. Daily oscillations in mammalian physiology are generated through an intrinsic molecular‐clock mechanism. An unresolved phenomenon in the field of circadian rhythms is the underlying mechanism(s) that allow the core molecular‐clock proteins (Bmal1/Clock common across all cell types) to transcriptionally target genes in a tissue‐specific fashion. The goal of this project was to use a targeted approach in skeletal muscle to identify mechanisms in which the molecular‐clock regulates the transcription of skeletal muscle specific genes. We focused our study on the molecular regulation of the muscle specific z‐line gene Titin‐cap (T‐cap). We choose this gene because it is highly circadian in skeletal muscle, it is known to be regulated downstream of the myogenic regulatory factor MyoD1 in skeletal muscle and its expression is significantly down‐regulated in the muscle of Bmal1 KO mice. Utilizing T‐cap promoter‐reporter contstructs in C2C12 myotubes, we demonstrate that the T‐cap promoter contains essential elements required for circadian oscillation in vitro (absence of environmental time cues) suggestive of a direct clock‐controlled gene. We performed a series of transfection experiments testing T‐cap promoter‐reporter constructs in C2C12 myotubes, and demonstrated that T‐cap is transactivated by overexpression of clock factors BMAL1:CLOCK, as well as MyoD1. We demonstrate that the T‐cap promoter contains essential elements required for circadian oscillation in vitro (absence of environmental time cues) suggestive of a direct clock‐controlled gene. Overexpression of MyoD1 was sufficient to enhance the amplitude of the T‐cap promoter‐reporter rhythm without affecting the circadian phase or period length. Interestingly, co‐transfection studies with mutant forms of Bmal1 or MyoD1, showed that BMAL1:CLOCK and MyoD1 work in a synergistic fashion and require each other to promote the circadian expression of T‐cap in C2C12 myotubes. Deletion constructs and mutagenesis studies followed by ChIP assays demonstrated that both BMAL1 and MyoD1 were bound to the proximal promoter of T‐cap, and we identified a tandem E‐box element required for T‐cap circadian expression. These results demonstrate that the molecular‐clock factors, BMAL1 and CLOCK, work with MyoD1, a tissue‐specific transcription factor, to promote the circadian expression of T‐cap in skeletal muscle. On going studies are aimed at elucidating the molecular basis underlying the synergist interaction observed between the molecular‐clock and MyoD1.Support or Funding InformationNIH RO1: AR066082
The Muscle Force Characteristics of SEMG in The Take‐off Phase of 100 m Hurdles Female Athlete
Authors: Sun Youping , He Jing , Wang Li 
Published: November 2023

OBJECTIVEReveal the characteristics of muscle force of 100 m hurdles female athlete inMETHODSSurface electromyography (sEMG) signals are widely used to evaluate muscle force, In this work, a100 m hurdles female athlete has been made to analyze the complexity of sEMG signals in take‐off phase. 16 muscle were Selected in study, for example the deltoid toe, beam under the rectus, vastus lateral's muscle, erector spinae, gluteus maximums muscle, semitendinosus muscle, medial head of gastrocnemius muscle, tensor fascia lata and so on.RESULTSThe sequence major muscle forcibly of the hurdle step skill in different stages as follows. In take‐off phase: the under rectus abdomen of the lead leg ←the glute maximus of the swinging leg ←the semitendinosus muscle of the lead leg← the deltoid toe of the lead leg. In flight phase: the under rectus abdomen of the lead leg ←the tensor fasciae latae muscle of the swinging leg ←the glute maximus of the swinging leg←the deltoid toe of the lead leg. In touch‐down phase: the glute maximus of the swinging leg ←the musculus semitendinosus of the swinging leg←the musculus semitendinosus of lead leg←the deltoid toe of the swinging leg.CONCLUSIONIt is found that the under rectus abdomen of the lead leg is the major muscle in take‐off phase, and the under rectus abdomen of the lead leg is the major muscle in flight phase, and the glute maximus of the swinging leg is the major muscle.Support or Funding InformationThe key lab of adolescent health intervention and exercise assessment, Ministry of China
Chronic Binge Alcohol (CBA) Administration Increases Protein Tyrosine Phosphatase 1B (PTP1B) Protein Expression in Fed Simian Immunodeficiency Virus (SIV) Infected Rhesus Macaques
Authors: Ford Stephen M. , Simon Liz , Stouwe Curtis Vande , Allerton Tim , Dufour Jason P. , Nelson Steve , Bagby Gregory J. , Molina Patricia E. 
Published: November 2023

Chronic alcohol consumption, HIV infection, and anti‐retroviral therapy (ART) have independently been shown to impair whole body insulin responsiveness. Previous studies from our group have shown that skeletal muscle of CBA administered SIV‐infected (CBA/SIV) male rhesus macaques has upregulated ubiquitin‐proteasome pathway activity, enhanced pro‐inflammatory cytokine, and suppressed IGF‐I expression at end stage SIV infection. These findings suggest that CBA may impair insulin‐mediated anabolic responses at end‐stage disease. Whether systemic and skeletal muscle metabolic alterations are present at earlier time points of SIV infection or are affected by ART administration was not known. In this study, we tested the hypothesis that CBA decreases whole body insulin sensitivity and insulin signaling in the skeletal muscle during the asymptomatic stage of SIV infection in male rhesus macaques and proposed that this would be further aggravated by ART. CBA or sucrose (SUC) was administered intragastrically for 3 mos prior to inoculation with SIVmac251 and continued until necropsy. At 2.5 mos. post‐SIV infection, daily administration of ART (tenofovir and emtricitabine) was initiated in half of the SUC/SIV and CBA/SIV macaques. Frequently sampled intravenous glucose tolerance tests were performed to analyze glucose‐insulin dynamics, including acute insulin response to glucose (AIRg), disposition index (DI), and insulin sensitivity index, using a homeostatic model. One week prior to necropsy, a controlled feeding protocol was performed with infusion of a Carnation breakfast supplement (9.283 mL/kg/h) beginning 1.5 hours after CBA or SUC administration, continued for one hour, followed by a quadriceps femoris biopsy. One week after the feeding protocol, fasted‐state muscle biopsy was collected. At study endpoint (14 mo CBA, 11 mo SIV) CBA/SIV macaques had a significantly reduced (p<0.05) AIRg and DI and circulating levels of adiponectin, relative to SUC/SIV macaques, irrespective of ART status. Western blot analysis of fasted‐and fed‐state skeletal muscle samples revealed a statistically significant increase in fed‐state PTP1B, a negative regulator of insulin signaling, in CBA/SIV relative to SUC/SIV macaques and irrespective of ART status. These findings suggest that CBA impairs insulin‐mediated effects in CBA/SIV macaques and warrant future studies elucidating the specific alterations in the insulin signaling cascade that are modulated by CBA.Support or Funding InformationThe work was supported by National Institutes of Health (NIH) grants: P60AA09803, T32AA07577, and F30AA024030‐01A1.
Quantification and Characterization of Type I Myofiber Grouping: the Effect of Aging
Authors: Hammond Kelley G , Kelly Neil A , Bickel C. Scott , Bamman Marcas M 
Published: November 2023

Among the neuromuscular changes that occur with aging, older adults may experience neuronal death, which is revealed through sarcopenia and motor unit loss. However, motor unit loss may not always elicit myofiber death, as some denervated myofibers are reinnervated by another local motor neuron and incorporated into that motor unit. This reorganization of motor units can facilitate the integration of type IIa myofibers into a type I motor unit, causing those fibers to express slow myosin heavy chain (MHC; type I). This denervation/reinnervation and subsequent myofiber type shift can result in type I myofiber grouping.PURPOSETo characterize grouped versus ungrouped type I myofibers by morphological and functional features in older adults.METHODSMuscle tissue specimens were collected from the vastus lateralis, and myofibers were assessed by MHC expression (I, IIa, IIx) for type, size, and grouping. Grouping was determined using a statistical model which includes type I distribution and nearest‐neighbor methods. Capillarization was assessed by immunohistochemistry.RESULTSPercent of grouped type I myofibers is higher in Old compared to Young (51.7% vs. 21.4%; p<0.001). The average number of myofibers per group is higher in Old than Young adults (56.6 vs 13.3; p=0.01). In Older adults, grouped type I myofibers are significantly larger than ungrouped (4911 vs. 4335 μm2; p<0.001), and have fewer capillary contacts per myofiber (2.4 vs. 3.7; p<0.001).CONCLUSIONAge‐related changes to skeletal muscle includes an increase in type I myofiber grouping. This grouping is characterized by increased myofiber size and decreased capillarity in grouped type I myofibers.Support or Funding InformationSupported by NIH Grant T32HD071866 and the UAB Center for Exercise Medicine
Does Titin Explain The High Passive Force Observed in Frog Tibialis Anterior Muscle?
Authors: Joumaa Venus , Kim Si Yong , Seerattan Ruth , Herzog Walter 
Published: November 2023

INTRODUCTIONThe force‐length relationship of various skeletal muscles indicates that passive force is generally much lower than active force [1]. However, a previous study showed that the whole frog tibialis anterior (TA) muscle has significantly higher passive than active forces within its normal range of motion (Figure 1) [2].It is known that titin, the giant protein within the sarcomere, is a main contributor to passive force in skeletal muscle at rest [3]. Furthermore, variations in titin isoforms have been related to different passive forces; the shorter the titin isoform, the higher the passive force [3, 4]. Therefore, the high passive force observed in frog TA muscle could result from the expression of a short titin isoform and thus a high titin‐based passive force.The purpose of this study was to investigate titin isoforms and titin‐based passive force in frog TA muscle. Titin‐based passive force was determined by testing passive force in single skinned muscle fibres in which titin is considered to be the major source of passive force [3].METHODSTitin isoforms: Titin isoforms in frog TA and rabbit psoas muscles were determined using agarose strengthened 2% acrylamide SDS‐PAGE gels.Skinned fibre experiment: Active and passive force‐length relationships were established by stretching skinned frog TA fibres (n=10) to various sarcomere lengths (2.4, 2.6, 2.8, 3.0, 3.2, 3.4 and 3.6 μm), and isometrically activating them after steady state force had been reached.RESULTSThe frog TA expresses two titin isoforms similar to those expressed by rabbit psoas muscle (3.3 and 3.40 MD).The active and passive force‐length relationships in TA skinned fibres indicate that passive force is significantly lower than active force on the descending limb of the force‐length relationship (Figure 2).DISCUSSION AND CONCLUSIONSFrog TA titin isoforms are not different from those of rabbit psoas, which are known to have relatively low passive [3, 4] compared to active force. Single skinned fibres isolated from frog TA muscle do not produce high passive compared to active forces. Therefore, it seems that titin is not responsible for the high passive force observed at the whole frog TA muscle level. It is likely that the high passive forces produced by the frog TA muscle originate from the extracellular matrix rather than structures within the fibres.The high passive forces found for the entire frog TA muscle might have implications for the function of the muscle during swimming. Since frogs have large webbed feet, a high passive force in the TA allows frogs to use their feet like human swimmers use passive fins to increase the speed and decrease the energy expenditure of swimming.Support or Funding InformationCIHR, NSERC, AIHS