138 results on '"Esther E. Dupont-Versteegden"'
Search Results
2. Extracellular vesicle distribution and localization in skeletal muscle at rest and following disuse atrophy
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Ahmed Ismaeel, Douglas W. Van Pelt, Zachary R. Hettinger, Xu Fu, Christopher I. Richards, Timothy A. Butterfield, Jonathan J. Petrocelli, Ivan J. Vechetti, Amy L. Confides, Micah J. Drummond, and Esther E. Dupont-Versteegden
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Orthopedics and Sports Medicine ,Cell Biology ,Molecular Biology - Abstract
Background Skeletal muscle (SkM) is a large, secretory organ that produces and releases myokines that can have autocrine, paracrine, and endocrine effects. Whether extracellular vesicles (EVs) also play a role in the SkM adaptive response and ability to communicate with other tissues is not well understood. The purpose of this study was to investigate EV biogenesis factors, marker expression, and localization across cell types in the skeletal muscle. We also aimed to investigate whether EV concentrations are altered by disuse atrophy. Methods To identify the potential markers of SkM-derived EVs, EVs were isolated from rat serum using density gradient ultracentrifugation, followed by fluorescence correlation spectroscopy measurements or qPCR. Single-cell RNA sequencing (scRNA-seq) data from rat SkM were analyzed to assess the EV biogenesis factor expression, and cellular localization of tetraspanins was investigated by immunohistochemistry. Finally, to assess the effects of mechanical unloading on EV expression in vivo, EV concentrations were measured in the serum by nanoparticle tracking analysis in both a rat and human model of disuse. Results In this study, we show that the widely used markers of SkM-derived EVs, α-sarcoglycan and miR-1, are undetectable in serum EVs. We also found that EV biogenesis factors, including the tetraspanins CD63, CD9, and CD81, are expressed by a variety of cell types in SkM. SkM sections showed very low detection of CD63, CD9, and CD81 in myofibers and instead accumulation within the interstitial space. Furthermore, although there were no differences in serum EV concentrations following hindlimb suspension in rats, serum EV concentrations were elevated in human subjects after bed rest. Conclusions Our findings provide insight into the distribution and localization of EVs in SkM and demonstrate the importance of methodological guidelines in SkM EV research.
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- 2023
3. The transcript interactome of skeletal muscle <scp>RNA</scp> binding protein motif 3 ( <scp>RBM3</scp> )
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Zachary R. Hettinger, Amy L. Confides, Peter W. Vanderklish, and Esther E. Dupont‐Versteegden
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Physiology ,Physiology (medical) - Published
- 2023
4. Temporal disruption of neuromuscular communication and muscle atrophy following noninvasive ACL injury in rats
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Cale A. Jacobs, Steven M. Davi, Douglas W. Van Pelt, Amy L. Confides, Esther E. Dupont-Versteegden, Christian Lattermann, Kaleigh Clark, Kimberly A Buckholts, Emily R. Hunt, Timothy A. Butterfield, Cassandra N. Parise, and Lindsey K. Lepley
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Male ,medicine.medical_specialty ,Physiology ,Vastus lateralis muscle ,Anterior cruciate ligament ,Neuromuscular junction ,Quadriceps Muscle ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Rats, Long-Evans ,Longitudinal Studies ,Quadriceps muscle atrophy ,Denervation ,business.industry ,Anterior Cruciate Ligament Injuries ,Communication ,medicine.disease ,ACL injury ,Muscle atrophy ,Rats ,Muscular Atrophy ,medicine.anatomical_structure ,Endocrinology ,Neural cell adhesion molecule ,medicine.symptom ,business ,Research Article - Abstract
Many patients with anterior cruciate ligament (ACL) injuries have persistent quadriceps muscle atrophy, even after considerable time in rehabilitation. Understanding the factors that regulate muscle mass, and the time course of atrophic events, is important for identifying therapeutic interventions. With a noninvasive animal model of ACL injury, a longitudinal study was performed to elucidate key parameters underlying quadriceps muscle atrophy. Male Long-Evans rats were euthanized at 6, 12, 24, or 48 h or 1, 2, or 4 wk after ACL injury that was induced via tibial compression overload; controls were not injured. Vastus lateralis muscle size was determined by wet weight and fiber cross-sectional area (CSA). Evidence of disrupted neuromuscular communication was assessed via the expression of neural cell adhesion molecule (NCAM) and genes associated with denervation and neuromuscular junction instability. Abundance of muscle RING-finger protein-1 (MuRF-1), muscle atrophy F-box (MAFbx), and 45 s pre-rRNA along with 20S proteasome activity were determined to investigate mechanisms related to muscle atrophy. Finally, muscle damage-related parameters were assessed by measuring IgG permeability, centronucleation, CD68 mRNA, and satellite cell abundance. When compared with controls, we observed a greater percentage of NCAM-positive fibers at 6 h postinjury, followed by higher MAFbx abundance 48 h postinjury, and higher 20S proteasome activity at 1 wk postinjury. A loss of muscle wet weight, smaller fiber CSA, and the elevated expression of run-related transcription factor 1 (Runx1) were also observed at the 1 wk postinjury timepoint relative to controls. There also were no differences observed in any damage markers. These results indicate that alterations in neuromuscular communication precede the upregulation of atrophic factors that regulate quadriceps muscle mass early after noninvasive ACL injury. NEW & NOTEWORTHY A novel preclinical model of ACL injury was used to establish that acute disruptions in neuromuscular communication precede atrophic events. These data help to establish the time course of muscle atrophy after ACL injury, suggesting that clinical care may benefit from the application of acute neurogenic interventions and early gait reloading strategies.
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- 2022
5. Skeletal Muscle Nuclei in Mice are not Post-mitotic
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Agnieszka K Borowik, Arik Davidyan, Frederick F Peelor, Evelina Voloviceva, Stephen M Doidge, Matthew P Bubak, Christopher B Mobley, John J McCarthy, Esther E Dupont-Versteegden, and Benjamin F Miller
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Cell Nucleus ,Mice ,Polyesters ,Muscle Fibers, Skeletal ,Animals ,Muscle, Skeletal ,Quadriceps Muscle - Abstract
The skeletal muscle research field generally accepts that nuclei in skeletal muscle fibers (i.e., myonuclei) are post-mitotic and unable to proliferate. Because our deuterium oxide (D2O) labeling studies showed DNA synthesis in skeletal muscle tissue, we hypothesized that resident myonuclei can replicatein vivo. To test this hypothesis, we used a mouse model that temporally labeled myonuclei with GFP followed by D2O labeling during normal cage activity, functional overload, and with satellite cell ablation. During normal cage activity, we observed deuterium enrichment into myonuclear DNA in 7 out of 7 plantaris (PLA), 6 out of 6 tibialis anterior (TA), 5 out of 7 gastrocnemius (GAST) and 7 out of 7 quadriceps (QUAD). The average fractional synthesis rates (FSR) of DNA in myonuclei were: 0.0202 ± 0.0093 in PLA, 0.0239 ± 0.0040 in TA, 0.0076 ± 0. 0058 in GAST, and 0.0138 ± 0.0039 in QUAD, while there was no replication in myonuclei from EDL. These FSR values were largely reproduced in the overload and satellite cell ablation conditions although there were higher synthesis rates in the overloaded PLA muscle. We further provided evidence that myonuclear replication is through endoreplication that results in polyploidy. These novel findings contradict the dogma that skeletal muscle nuclei are post-mitotic and open potential avenues to harness the intrinsic replicative ability of myonuclei for muscle maintenance and growth.Graphical Abstract
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- 2022
6. Age-Related Susceptibility to Muscle Damage Following Mechanotherapy in Rats Recovering From Disuse Atrophy
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Amy L. Confides, Esther E. Dupont-Versteegden, Kyoko Hamagata, Benjamin F. Miller, Zachary R. Hettinger, Timothy A. Butterfield, and Marcus M. Lawrence
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Male ,THE JOURNAL OF GERONTOLOGY: Biological Sciences ,Aging ,medicine.medical_specialty ,Gastrocnemius muscle ,Atrophy ,Internal medicine ,Myosin ,medicine ,Animals ,Muscle, Skeletal ,business.industry ,Age Factors ,Protein turnover ,Skeletal muscle ,Hindlimb Suspension ,medicine.disease ,Muscular Disorders, Atrophic ,Rats, Inbred F344 ,Rats ,Muscular Atrophy ,Endocrinology ,medicine.anatomical_structure ,Geriatrics and Gerontology ,business ,Mechanotherapy ,Disuse atrophy - Abstract
The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14 days of hindlimb suspension, followed by 7 days of recovery with (RE + M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross-sectional area were observed between RE and RE + M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin−/laminin+ fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.
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- 2021
7. Efficacy of power training to improve physical function in individuals diagnosed with frailty and chronic disease: A meta-analysis
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Alexander B. Sklivas, Lauren E. Robinson, Timothy L. Uhl, Esther E. Dupont‐Versteegden, and Kirby P. Mayer
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Adult ,Frailty ,Physiology ,Physiology (medical) ,Chronic Disease ,Humans ,Resistance Training ,Middle Aged ,Exercise ,Aged ,Exercise Therapy - Abstract
Muscle power training with emphasis on high-velocity of concentric movement improves physical functionality in healthy older adults, and, maybe superior to traditional exercise programs. Power training may also be advantageous for patients with acute and chronic illnesses, as well as frail individuals. To determine the efficacy of power training compared with traditional resistance training on physical function outcomes in individuals diagnosed with frailty, acute illness or chronic disease. PubMed (MEDLINE), CINAHL, PEDro, Web of Science, and Google Scholar. (1) at least one study group receives muscle power training of randomized controlled trial (RCT) (2) study participants diagnosed as prefrail, frail or have an ongoing acute or chronic disease, condition or illness; (3) study participants over the age of 18; (4) publication in English language; (5) included physical function as the primary or secondary outcome measures. Two independent reviewers assessed articles for inclusion and graded the methodological quality using Cochrane Risk-of-Bias tool for RCTs. Fourteen RCTs met the inclusion criteria. In seven studies, muscle power training was more effective at improving physical function compared to control activities with a mean fixed effect size (ES) of 0.41 (p = 0.006; 95% CI 0.12 to 0.71). Power training and conventional resistance training had similar effectiveness in eight studies with a mean fixed ES of 0.10 (p = 0.061; 95% CI -0.01 to 0.40). Muscle power training is just as efficacious for improving physical function in individuals diagnosed with frailty and chronic disease when compared to traditional resistance training. The advantages of power training with reduced work per session may support power training as a preferential exercise modality for clinical populations. The findings should be interpreted with caution since generalizability is questioned due to the heterogeneity of patient populations enrolled and participants were relatively mobile at baseline.
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- 2022
8. Impaired Proteostasis, not Protein Synthesis, Limits Recovery of Aged Skeletal Muscle After Disuse Atrophy
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Jordan D. Fuqua, Marcus M. Lawrence, Zachary Hettinger, Agnieszka K. Borowik, Frederick F. Peelor, Amy L. Confides, Esther E. Dupont‐Versteegden, and Benjamin F. Miller
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
9. Myonuclei Can Replicate DNA
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Agnieszka K. Borowik, Frederick F. Peelor, Esther E. Dupont‐Versteegden, John J. McCarthy, and Benjamin F. Miller
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
10. Ribosome biogenesis and degradation regulate translational capacity during muscle disuse and reloading
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Benjamin F. Miller, David Cameron-Smith, Marcus M. Lawrence, Cameron J. Mitchell, Randall F. D'Souza, Esther E. Dupont-Versteegden, James F. Markworth, Douglas W. Van Pelt, John J. McCarthy, Sally D. Poppitt, Nina Zeng, and Vandre C. Figueiredo
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0301 basic medicine ,Male ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Regrowth ,Muscle hypertrophy ,lcsh:QM1-695 ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Transcription (biology) ,Physiology (medical) ,Internal medicine ,medicine ,Protein biosynthesis ,Animals ,Orthopedics and Sports Medicine ,Muscle, Skeletal ,business.industry ,RNA ,Skeletal muscle ,lcsh:Human anatomy ,Original Articles ,medicine.disease ,Ribophagy ,Muscle atrophy ,Resistance training ,Rats ,Muscular Atrophy ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Ribosomal RNA ,Hindlimb Suspension ,030220 oncology & carcinogenesis ,Sarcopenia ,Protein Biosynthesis ,Original Article ,medicine.symptom ,lcsh:RC925-935 ,business ,Ribosomes - Abstract
Background Translational capacity (i.e. ribosomal mass) is a key determinant of protein synthesis and has been associated with skeletal muscle hypertrophy. The role of translational capacity in muscle atrophy and regrowth from disuse is largely unknown. Therefore, we investigated the effect of muscle disuse and reloading on translational capacity in middle‐aged men (Study 1) and in rats (Study 2). Methods In Study 1, 28 male participants (age 50.03 ± 3.54 years) underwent 2 weeks of knee immobilization followed by 2 weeks of ambulatory recovery and a further 2 weeks of resistance training. Muscle biopsies were obtained for measurement of total RNA and pre‐ribosomal (r)RNA expression, and vastus lateralis cross‐sectional area (CSA) was determined via peripheral quantitative computed tomography. In Study 2, male rats underwent hindlimb suspension (HS) for either 24 h (HS 24 h, n = 4) or 7 days (HS 7d, n = 5), HS for 7 days followed by 7 days of reloading (Rel, n = 5) or remained as ambulatory weight bearing (WB, n = 5) controls. Rats received deuterium oxide throughout the study to determine RNA synthesis and degradation, and mTORC1 signalling pathway was assessed. Results Two weeks of immobilization reduced total RNA concentration (20%) and CSA (4%) in men (both P ≤ 0.05). Ambulatory recovery restored total RNA concentration to baseline levels and partially restored muscle CSA. Total RNA concentration and 47S pre‐rRNA expression increased above basal levels after resistance training (P ≤ 0.05). In rats, RNA synthesis was 30% lower while degradation was ~400% higher in HS 7d in soleus and plantaris muscles compared with WB (P ≤ 0.05). mTORC1 signalling was lower in HS compared with WB as was 47S pre‐rRNA (P ≤ 0.05). With reloading, the aforementioned parameters were restored to WB levels while RNA degradation was suppressed (P ≤ 0.05). Conclusions Changes in RNA concentration following muscle disuse and reloading were associated with changes in ribosome biogenesis and degradation, indicating that both processes are important determinants of translational capacity. The pre‐clinical data help explain the reduced translational capacity after muscle immobilization in humans and demonstrate that ribosome biogenesis and degradation might be valuable therapeutic targets to maintain muscle mass during disuse.
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- 2020
11. Optimizing Outcomes With Physical Therapy Treatment for IndividuALs Surviving an Intensive Care Units Admission for COVID-19 (OPTImAL)—A Protocol for a Single Center Prospective Study
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Ashley A. Montgomery, Kirby P. Mayer, Angela K Steele, Esther E. Dupont-Versteegden, Peter E. Morris, Rajan R. Joshi, Selina M Parry, and Melissa K. Soper
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Protocol (science) ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Intensive care ,Emergency medicine ,medicine ,Physical Therapy, Sports Therapy and Rehabilitation ,business ,Single Center ,Prospective cohort study - Published
- 2020
12. Cold shock RNA-binding protein RBM3 as a potential therapeutic target to prevent skeletal muscle atrophy
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Douglas W. Van Pelt, Zachary R. Hettinger, and Esther E. Dupont-Versteegden
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Muscle atrophy is among the most common conditions during sickness, injury, aging and after orthopedic surgeries, and is associated with poor health outcomes. As such, it is important to understand the molecular machinery responsible for the control of muscle mass and function for development of therapeutic targets and strategies to combat muscle atrophy. We have identified the cold shock RNA binding protein, RNA-binding motif protein 3 (RBM3) as a critical regulatory node in the control of skeletal muscle mass and herein, we review our current knowledge of its actions in skeletal muscle. We also cover future directions of research and how this knowledge may translate into therapeutic interventions.
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- 2020
13. Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading
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Zachary R. Hettinger, Marcus M. Lawrence, Amy L. Confides, Justin J. Reid, Timothy A. Butterfield, Douglas W. Van Pelt, Esther E. Dupont-Versteegden, Frederick F. Peelor, Jaime L. Laurin, Emily R. Hunt, and Benjamin F. Miller
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Male ,Aging ,medicine.medical_specialty ,Anabolism ,Atrophy ,Rats, Inbred BN ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,Massage ,business.industry ,Protein turnover ,Skeletal muscle ,medicine.disease ,Rats, Inbred F344 ,Rats ,Muscular Atrophy ,Endocrinology ,medicine.anatomical_structure ,Hindlimb Suspension ,Original Article ,Geriatrics and Gerontology ,Myofibril ,Mechanotherapy ,business ,Disuse atrophy - Abstract
Massage is a viable mechanotherapy to improve protein turnover during disuse atrophy and improve muscle regrowth during recovery from disuse atrophy in adult muscle. Therefore, we investigated whether massage can cause beneficial adaptations in skeletal muscle from aged rats during normal weight-bearing (WB) conditions, hindlimb suspension (HS), or reloading (RE) following HS. Aged (30 months) male Fischer 344/Brown Norway rats were divided into two experiments: (1) WB for 7 days (WB, n = 8), WB with massage (WBM, n = 8), HS for 7 days (HS7, n = 8), or HS with massage (HSM, n = 8), and (2) WB for 14 days (WB14, n = 8), HS for 14 days (HS14, n = 8), reloading (RE, n = 10), or reloading with massage (REM, n = 10) for 7 days following HS. Deuterium oxide (D(2)O) labeling was used to assess dynamic protein and ribosome turnover in each group and anabolic signaling pathways were assessed. Massage did have an anabolic benefit during RE or WB. In contrast, massage during HS enhanced myofibrillar protein turnover in both the massaged limb and contralateral non-massaged limb compared with HS, but this did not prevent muscle loss. Overall, the data demonstrate that massage is not an effective mechanotherapy for prevention of atrophy during muscle disuse or recovery of muscle mass during reloading in aged rats. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00215-y) contains supplementary material, which is available to authorized users.
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- 2020
14. Depletion of resident muscle stem cells negatively impacts running volume, physical function, and muscle fiber hypertrophy in response to lifelong physical activity
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Esther E. Dupont-Versteegden, Vandre C. Figueiredo, John J. McCarthy, Charlotte A. Peterson, Ivan J. Vechetti, Davis A. Englund, Kevin A. Murach, and Cory M. Dungan
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0301 basic medicine ,medicine.medical_specialty ,RNA, Untranslated ,Time Factors ,Satellite Cells, Skeletal Muscle ,Physiology ,Muscle Fibers, Skeletal ,Physical activity ,Skeletal muscle adaptation ,Mice, Transgenic ,Physical function ,Biology ,Stimulus (physiology) ,Running ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Physical Conditioning, Animal ,Internal medicine ,medicine ,Animals ,Diphtheria Toxin ,PAX7 Transcription Factor ,Skeletal muscle ,Hypertrophy ,Cell Biology ,Adaptation, Physiological ,Peptide Fragments ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,Female ,Muscle fiber hypertrophy ,Sedentary Behavior ,Stem cell ,Glycolysis ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Research Article - Abstract
To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a nontranslational stimulus and/or have been performed over a relatively short time frame. Although it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long-term physical activity. The current study was designed to determine whether reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-diphtheria toxin A (DTA) mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 mo. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume, and the size of muscle proprioceptors (spindle fibers). Furthermore, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of G protein-coupled receptor (GPCR) signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long-term physical activity. These findings suggest that satellite cells play a role in preserving physical function during aging and influence muscle adaptation during sustained periods of physical activity.
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- 2020
15. Interrater Reliability of Muscle Ultrasonography Image Acquisition by Physical Therapists in Patients Who Have or Who Survived Critical Illness
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Aaron Denham, Kirby P. Mayer, Peter E. Morris, Sanjay Dhar, Esther E. Dupont-Versteegden, Evan Cassity, and Johnny England
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Adult ,Male ,Students, Health Occupations ,medicine.medical_specialty ,Intraclass correlation ,Critical Illness ,Physical Therapy, Sports Therapy and Rehabilitation ,Biceps ,Quadriceps Muscle ,law.invention ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,law ,medicine ,Humans ,Ultrasonics ,Survivors ,Muscle, Skeletal ,Wasting ,Reliability (statistics) ,Aged ,Ultrasonography ,Aged, 80 and over ,Observer Variation ,business.industry ,Reproducibility of Results ,030208 emergency & critical care medicine ,Middle Aged ,Intensive care unit ,Physical Therapists ,Inter-rater reliability ,Cross-Sectional Studies ,Sonographer ,Physical therapy ,Female ,Observational study ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Objective Previous studies have demonstrated that muscle ultrasound (US) can be reliably performed at the patient bedside by novice assessors with minimal training. The primary objective of this study was to determine the interrater reliability of muscle US image acquisition by physical therapists and physical therapist students. Secondarily, this study was designed to elucidate the process for training physical therapists to perform peripheral skeletal muscle US. Methods This was a cross-sectional observational study. Four novices and 1 expert participated in the study. Novice sonographers engaged in a structured training program prior to implementation. US images were obtained on the biceps brachii, quadriceps femoris, and tibialis anterior muscles in 3 groups: patients in the intensive care unit, patients on the hospital ward, and participants in the outpatient gym who were healthy. Reliability of image acquisition was analyzed compared with the expert sonographer. Results Intraclass correlation coefficient values ranged from 0.76 to 0.97 with an average for all raters and all muscles of 0.903, indicating excellent reliability of image acquisition. In general, the experienced physical therapist had higher or similar intraclass correlation coefficient values compared with the physical therapist students in relation to the expert sonographer. Conclusions Excellent interrater reliability for US was observed regardless of the level of experience, severity of patient illness, or patient setting. These findings indicate that the use of muscle US by physical therapists can accurately capture reliable images in patients with a range of illness severity and different clinical practice settings across the continuum of care. Impact Physical therapists can utilize US to obtain images to assess muscle morphology. Lay Summary Physical therapists can use noninvasive US as an imaging tool to assess the size and quality of peripheral skeletal muscle. This study demonstrates that physical therapists can receive training to reliably obtain muscle images in patients admitted to the intensive care unit who may be at risk for muscle wasting and may benefit from early rehabilitation.
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- 2020
16. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans
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Amy L. Confides, Esther E. Dupont-Versteegden, Hemendra J. Vekaria, Brian S. Finlin, Philip A. Kern, Patrick G. Sullivan, Hasiyet Memetimin, Jianzhong Chen, Riham H. El Khouli, Philip M. Westgate, Andrew J. Morris, Beibei Zhu, and Zachary R. Johnson
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Adult ,Blood Glucose ,Male ,0301 basic medicine ,medicine.medical_specialty ,Biopsy ,Adipose tissue ,Adrenergic beta-3 Receptor Agonists ,White adipose tissue ,Carbohydrate metabolism ,03 medical and health sciences ,0302 clinical medicine ,Commentaries ,Internal medicine ,Brown adipose tissue ,Adipocytes ,medicine ,Humans ,Glucose homeostasis ,Lipolysis ,Obesity ,Muscle, Skeletal ,Aged ,business.industry ,Skeletal muscle ,General Medicine ,Adipose Tissue, Beige ,Middle Aged ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Thiazoles ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Commentary ,Acetanilides ,Female ,business ,Mirabegron ,medicine.drug - Abstract
BACKGROUNDBeige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODSBefore and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTSThe clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSIONMirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATIONClinicaltrials.gov NCT02919176.FUNDINGNIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.
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- 2020
17. Age-related responses to a bout of mechanotherapy in skeletal muscle of rats
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Timothy A. Butterfield, Sarah M. Abshire, Amy L. Confides, Emily R. Hunt, Esther E. Dupont-Versteegden, and Douglas W. Van Pelt
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Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,Physiology ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,Atrophy ,Rats, Inbred BN ,Physiology (medical) ,Age related ,medicine ,Animals ,HSP70 Heat-Shock Proteins ,Muscle, Skeletal ,Massage ,business.industry ,Extramural ,RNA-Binding Proteins ,Skeletal muscle ,medicine.disease ,Rats, Inbred F344 ,Rats ,Muscular Atrophy ,030104 developmental biology ,medicine.anatomical_structure ,Mechanotherapy ,business ,030217 neurology & neurosurgery ,Signal Transduction ,Research Article - Abstract
Cyclic compressive loading (CCL) is a massage mimetic that improves muscle regrowth from atrophy in adult rats. Therefore, we tested if a single bout of CCL increases anabolic signaling and protein synthesis in muscle during normal, weight-bearing conditions in gastrocnemius muscle from adult and aged rats. Male Brown Norway/F344 rats at 10 (adult) and 30 (aged) months of age were assigned control or CCL (receiving a single bout of CCL). Twenty-four hours following a single bout of CCL there was no change in protein synthesis, Akt, or GSK3β signaling at either age, despite adult rats having higher abundance and activation of mechanosensitive pathways (integrins and integrin-linked kinase). Murf1 was elevated in response to CCL in both age groups, potentially indicating muscle remodeling. Muscle from aged rats exhibited an increase in heat shock protein (HSP) 25 and HSP70 and in the cold shock protein RNA-binding motif 3 (RBM3), demonstrating a unique stress response to CCL in aged muscle only. Finally, muscle from aged rats exhibited higher basal protein synthesis that was corroborated by elevated eIF2Bε and rpS6 signaling, without an additional effect of CCL. In summary, a single bout of CCL does not have anabolic effects on skeletal muscle during normal, weight-bearing conditions, even though it has previously been shown to improve regrowth from atrophy. These data demonstrate that interventions that may help recover from atrophy do not necessarily induce muscle hypertrophy in unperturbed conditions. NEW & NOTEWORTHY Massage has been demonstrated to be an effective mechanotherapy to improve recovery from atrophy in adult skeletal muscle; however, this study shows that a single bout of massage fails to increase protein synthesis or anabolic signaling in adult or aged skeletal muscle during normal, weight-bearing conditions. Altogether, our data suggest massage is a useful mechanotherapy for preserving skeletal muscle when combined with other interventions but is not an anabolic stimulus on its own.
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- 2019
18. Macrophages expressing uncoupling protein 1 increase in adipose tissue in response to cold in humans
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Brian S, Finlin, Hasiyet, Memetimin, Amy L, Confides, Beibei, Zhu, Philip M, Westgate, Esther E, Dupont-Versteegden, and Philip A, Kern
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Multidisciplinary ,Adipose Tissue, White ,Macrophages ,Science ,Antigens, Differentiation, Myelomonocytic ,food and beverages ,nutritional and metabolic diseases ,Receptors, Cell Surface ,Adipose Tissue, Beige ,Metabolic syndrome ,Article ,Cold Temperature ,Thinness ,Antigens, CD ,Humans ,Medicine ,Adipocytes, Beige ,Obesity ,Uncoupling Protein 1 ,hormones, hormone substitutes, and hormone antagonists - Abstract
Acute cold induces beige adipocyte protein marker expression in human subcutaneous white adipose tissue (SC WAT) from both the cold treated and contralateral leg, and the immune system regulates SC WAT beiging in mice. Cold treatment significantly increased the gene expression of the macrophage markers CD68 and 86 in SC WAT. Therefore, we comprehensively investigated the involvement of macrophages in SC WAT beiging in lean and obese humans by immunohistochemistry. Cold treatment significantly increased CD163/CD68 macrophages in SC WAT from the cold treated and contralateral legs of lean and obese subjects, and had similar effects on CD206/CD68 macrophages, whereas the effects on CD86/CD68 macrophages were inconsistent between lean and obese. However, linear regression analysis did not find significant relationships between the change in macrophage numbers and the change in UCP1 protein abundance. A high percentage of CD163 macrophages in SC WAT expressed UCP1, and these UCP1 expressing CD163 macrophages were significantly increased by cold treatment in SC WAT of lean subjects. In conclusion, our results suggest that CD163 macrophages are involved in some aspect of the tissue remodeling that occurs during SC WAT beiging in humans after cold treatment, but they are likely not direct mediators of the beiging process.
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- 2021
19. Cross Talk rebuttal
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Tyler J. Kirby, Esther E. Dupont‐Versteegden, Physiology, ACS - Heart failure & arrhythmias, and AMS - Tissue Function & Regeneration
- Subjects
Muscular Atrophy ,Physiology ,Muscle Fibers, Skeletal ,Humans ,Muscle, Skeletal - Published
- 2022
20. Safety and Feasibility of an Interdisciplinary Treatment Approach to Optimize Recovery From Critical Coronavirus Disease 2019
- Author
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Melissa K. Soper, Esther E. Dupont-Versteegden, Selina M Parry, Megan L Lusby, Kirby P. Mayer, Anna G Kalema, Rajan R. Joshi, Angela K Steele, Peter E. Morris, and Ashley Montgomery-Yates
- Subjects
safety ,medicine.medical_specialty ,medicine.medical_treatment ,Telehealth ,law.invention ,coronavirus disease 2019 ,Quality of life ,Randomized controlled trial ,law ,cognitive dysfunction ,medicine ,Adverse effect ,Original Clinical Report ,implementation ,Depression (differential diagnoses) ,physical rehabilitation ,Rehabilitation ,RC86-88.9 ,business.industry ,Medical emergencies. Critical care. Intensive care. First aid ,General Medicine ,Clinical research ,intensive care unit recovery ,posttraumatic stress disorder ,postintensive care syndrome ,Emergency medicine ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Anxiety ,medicine.symptom ,business - Abstract
Supplemental Digital Content is available in the text., OBJECTIVES: Examine the safety and feasibility of a multimodal in-person or telehealth treatment program, administered in acute recovery phase for patients surviving critical coronavirus disease 2019. DESIGN: Pragmatic, pre-post, nonrandomized controlled trial with patients electing enrollment into one of the two recovery pathways. SETTING: ICU Recovery Clinic in an academic medical center. PATIENTS: Adult patients surviving acute respiratory failure due to critical coronavirus disease 2019. INTERVENTIONS: Patients participated in combined ICU Recovery clinic and 8 weeks of physical rehabilitation delivered: 1) in-person or 2) telehealth. Patients received medical care by an ICU Recovery Clinic interdisciplinary team and physical rehabilitation focused on aerobic, resistance, and respiratory muscle training. MEASUREMENTS AND MAIN RESULTS: Thirty-two patients enrolled with mean age 57 ± 12, 62% were male, and the median Sequential Organ Failure Assessment score was 9.5. There were no differences between the two groups except patients in telehealth pathway (n = 10) lived further from clinic than face-to-face patients (162 ± 60 vs 31 ± 47 kilometers, t = 6.06, p < 0.001). Four safety events occurred: one minor adverse event in the telehealth group, two minor adverse events, and one major adverse event in the in-person group. Three patients did not complete the study (two in-person and one telehealth). Six-minute walk distance increased to 101 ± 91 meters from pre to post (n = 29, t = 6.93, p < 0.0001), which was similar between the two groups (110 vs 80 meters, t = 1.34, p = 0.19). Self-reported levels of anxiety, depression, and distress were high in both groups with similar self-report quality of life. CONCLUSIONS: A multimodal treatment program combining care from an interdisciplinary team in an ICU Recovery Clinic with physical rehabilitation is safe and feasible in patients surviving the ICU for coronavirus disease 2019 acute respiratory failure.
- Published
- 2021
21. Fusion and beyond: Satellite cell contributions to loading-induced skeletal muscle adaptation
- Author
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John J. McCarthy, Esther E. Dupont-Versteegden, Kevin A. Murach, Charlotte A. Peterson, and Christopher S. Fry
- Subjects
Cell type ,Satellite Cells, Skeletal Muscle ,Regeneration (biology) ,Cell ,Muscle Fibers, Skeletal ,Skeletal muscle adaptation ,Skeletal muscle ,Biology ,biology.organism_classification ,Biochemistry ,Adaptation, Physiological ,Muscle hypertrophy ,medicine.anatomical_structure ,Genetics ,medicine ,Animals ,Humans ,Satellite (biology) ,Signal transduction ,Molecular Biology ,Neuroscience ,Biotechnology ,Signal Transduction - Abstract
Satellite cells support adult skeletal muscle fiber adaptations to loading in numerous ways. The fusion of satellite cells, driven by cell-autonomous and/or extrinsic factors, contributes new myonuclei to muscle fibers, associates with load-induced hypertrophy, and may support focal membrane damage repair and long-term myonuclear transcriptional output. Recent studies have also revealed that satellite cells communicate within their niche to mediate muscle remodeling in response to resistance exercise, regulating the activity of numerous cell types through various mechanisms such as secretory signaling and cell-cell contact. Muscular adaptation to resistance and endurance activity can be initiated and sustained for a period of time in the absence of satellite cells, but satellite cell participation is ultimately required to achieve full adaptive potential, be it growth, function, or proprioceptive coordination. While significant progress has been made in understanding the roles of satellite cells in adult muscle over the last few decades, many conclusions have been extrapolated from regeneration studies. This review highlights our current understanding of satellite cell behavior and contributions to adaptation outside of regeneration in adult muscle, as well as the roles of satellite cells beyond fusion and myonuclear accretion, which are gaining broader recognition.
- Published
- 2021
22. Disuse Atrophy Elevates Skeletal Muscle CD63 Expression and Ex Vivo Release of Extracellular Vesicles in a Muscle‐Specific Manner
- Author
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Timothy A. Butterfield, Douglas W. Van Pelt, and Esther E. Dupont-Versteegden
- Subjects
medicine.anatomical_structure ,CD63 ,Chemistry ,Genetics ,medicine ,Skeletal muscle ,Molecular Biology ,Biochemistry ,Extracellular vesicles ,Ex vivo ,Biotechnology ,Disuse atrophy ,Cell biology - Published
- 2021
23. Single Cell Transcriptomics Identifies Immunomodulation in Fibro‐Adipose Progenitor Cells and Changes to Macrophage Dynamics Following Mechanotherapy in Aged Rats Recovering From Disuse Muscle Atrophy
- Author
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Zachary R. Hettinger, Douglas Harrison, Esther E. Dupont-Versteegden, and Timothy A. Butterfield
- Subjects
Single cell transcriptomics ,Dynamics (mechanics) ,Genetics ,Disuse muscle atrophy ,Macrophage ,Adipose tissue ,Biology ,Progenitor cell ,Mechanotherapy ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2021
24. Using Massage to Combat Fear-Avoidance and the Pain Tension Cycle
- Author
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Anne D. Olson, Emily R. Hunt, Shelby E. Baez, Esther E. Dupont-Versteegden, and Timothy A. Butterfield
- Subjects
medicine.medical_specialty ,Massage ,Modality (human–computer interaction) ,business.industry ,Rehabilitation ,Return function ,Physical Therapy, Sports Therapy and Rehabilitation ,030229 sport sciences ,03 medical and health sciences ,0302 clinical medicine ,Physical therapy ,medicine ,Orthopedics and Sports Medicine ,business ,030217 neurology & neurosurgery - Abstract
Massage is a common therapeutic modality utilized by clinicians in a variety of settings to help treat injuries, reduce pain, and return function to patients. Massage benefits the patients both psychologically and physiologically, as patients report less pain and anxiety along with better mood and even decreased blood pressure following massage. Additionally, on the cellular level, massage has the ability to modulate the damaging inflammatory process and, in some cases, influence protein synthesis. Although massage has not been linked to a rehabilitation theory to date, this paper will propose how massage may influence fear-avoidance beliefs, or the patient’s inability to cope with pain that then leads to a pain tension cycle. Pain will often result in use avoidance, which creates muscle tension that further exacerbates the pain. Massage can affect the Fear-Avoidance Model because the beneficial effects of massage can break the cycle by either relieving the patient’s pain or eliminating the muscle tension. A modified Fear-Avoidance Model is presented that conceptualizes how pain and fear-avoidance lead to tension and muscle dysfunction. Massage has been incorporated into the model to demonstrate its potential for breaking the pain tension cycle. This model has the potential to be applied in clinical settings and provides an alternate treatment to patients with chronic pain who present with increased levels of fear-avoidance beliefs.
- Published
- 2019
25. Macrophage Regulation of Muscle Regrowth From Disuse in Aging
- Author
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Paul T. Reidy, Micah J. Drummond, and Esther E. Dupont-Versteegden
- Subjects
Aging ,medicine.medical_treatment ,Physical Therapy, Sports Therapy and Rehabilitation ,Article ,Muscle hypertrophy ,03 medical and health sciences ,Recovery period ,0302 clinical medicine ,Immune system ,Animals ,Humans ,Medicine ,Macrophage ,Orthopedics and Sports Medicine ,Muscle, Skeletal ,business.industry ,Macrophages ,Skeletal muscle ,Exercise therapy ,030229 sport sciences ,Immunotherapy ,Exercise Therapy ,Muscular Atrophy ,medicine.anatomical_structure ,Models, Animal ,Immunology ,business ,030217 neurology & neurosurgery - Abstract
Skeletal muscle immune cells, such as macrophages, are necessary for proper regrowth following muscle disuse. We suggest that the important role of macrophages concerning muscle regrowth following disuse is divergent compared to young mice (i.e. dysregulated) during the recovery period. Modulation of macrophages may be a promising future therapeutic target to enhance the impaired muscle growth during recovery from disuse in older adults.
- Published
- 2019
26. Loading in an Upright Tilting Hospital Bed Elicits Minimal Muscle Activation in Healthy Adults
- Author
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Kirby P. Mayer, Esther E. Dupont-Versteegden, Peter E. Morris, and Timothy L. Uhl
- Subjects
Hospital bed ,business.industry ,Anesthesia ,Rehabilitation ,Medicine ,Physical Therapy, Sports Therapy and Rehabilitation ,Muscle activation ,Critical Care and Intensive Care Medicine ,business - Published
- 2019
27. Physical Therapy Management of an Individual With Post-COVID Syndrome: A Case Report
- Author
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Melissa K. Soper, Anna G Kalema, Angela K Steele, Esther E. Dupont-Versteegden, Ashley Montgomery-Yates, Jill D Branton, Megan L Lusby, and Kirby P. Mayer
- Subjects
Adult ,medicine.medical_specialty ,Mindfulness ,medicine.medical_treatment ,Psychological intervention ,Walk Test ,Physical Therapy, Sports Therapy and Rehabilitation ,Metabolic equivalent ,Stress Disorders, Post-Traumatic ,03 medical and health sciences ,Post-Acute COVID-19 Syndrome ,0302 clinical medicine ,Quality of life (healthcare) ,Surveys and Questionnaires ,Humans ,Medicine ,Aerobic exercise ,Cognitive Dysfunction ,030212 general & internal medicine ,Posttraumatic Stress Disorder ,Pandemics ,Physical Therapy Modalities ,Rehabilitation ,SARS-CoV-2 ,business.industry ,COVID-19 ,Cognition ,Syndrome ,Dyspnea ,Orig Res Repor Other ,Quality of Life ,Physical therapy ,Anxiety ,Female ,AcademicSubjects/MED00110 ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Objective The purpose of this case report is to provide the clinical presentation and physical therapist management for a patient with post–COVID syndrome. Secondarily, the report highlights the importance of assessing cognitive and emotional health in patients with post–COVID syndrome. Methods (Case Description) A 37-year-old woman tested positive for SARS-CoV-2 and developed mild COVID-19 disease but did not require supplemental oxygen or hospitalization. The patient experienced persistent symptoms, including dyspnea, headaches, and cognitive fog. On day 62, they participated in an outpatient physical therapist evaluation that revealed deficits in exercise capacity, obtaining 50% of their age-predicted 6-minute walk distance. They had minor reductions in muscle strength and cognitive function. Self-reported quality of life was 50, and they scored above established cut-off scores for provisional diagnosis of posttraumatic stress disorder (PTSD). Results The patient participated in biweekly physical therapist sessions for 8 weeks, which included aerobic training, strengthening exercises, diaphragmatic breathing techniques, and mindfulness training. Metabolic equivalent for task levels increased with variability over the course of the program. The patient’s muscle strength, physical function, and exercise capacity improved. 6-Minute walk distance increased by 199 m, equating to 80% of their age-predicted distance. Quality of life and PTSD scores did not improve. At evaluation after physical therapy, the patient was still experiencing migraines, dyspnea, fatigue, and cognitive dysfunction. Conclusion This case report described the clinical presentation and physical therapist management of a person with post–COVID syndrome, a novel health condition for which little evidence exists to guide rehabilitation examination and interventions. Physical therapists should consider cognitive function and emotional health in their plan of care for patients with post–COVID syndromes. Impact This case alerts physical therapists to post–COVID syndrome—which can include debilitating symptoms of decreased aerobic tolerance, anxiety, PTSD, and cognitive dysfunction—and to the role that therapists can play in assessing these symptoms and managing these patients.
- Published
- 2021
28. Massage as a Mechanotherapy for Skeletal Muscle
- Author
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Esther E. Dupont-Versteegden, Marcus M. Lawrence, Douglas W. Van Pelt, Benjamin F. Miller, and Timothy A. Butterfield
- Subjects
Massage ,medicine.medical_specialty ,business.industry ,Skeletal muscle ,Physical Therapy, Sports Therapy and Rehabilitation ,030229 sport sciences ,Health benefits ,Article ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine.anatomical_structure ,medicine ,Humans ,Orthopedics and Sports Medicine ,business ,Mechanotherapy ,Muscle, Skeletal ,030217 neurology & neurosurgery - Abstract
Massage is anecdotally associated with many health benefits, but physiological and clinically relevant mechanisms recently have begun to be investigated in a controlled manner. Herein, we describe research supporting our hypothesis that massage can be used as a mechanotherapy imparting biologically relevant adaptations in skeletal muscle and improving muscle properties.
- Published
- 2021
29. BOOSTing patient mobility and function on a general medical unit by enhancing interprofessional care
- Author
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R Hogg Graham, Preetham Talari, Esther E. Dupont-Versteegden, Audrey M Johnson, Andrew Kelly, and J Kuperstein
- Subjects
Adult ,Male ,medicine.medical_specialty ,Quality management ,Science ,Bivariate analysis ,Patient Readmission ,Article ,Hospitals, University ,Treatment and control groups ,03 medical and health sciences ,Patient safety ,Medical research ,0302 clinical medicine ,Health care ,medicine ,Humans ,030212 general & internal medicine ,Early Ambulation ,Physical Therapy Modalities ,Aged ,Quality of Health Care ,Boosting (doping) ,Multidisciplinary ,business.industry ,030503 health policy & services ,Technician ,Length of Stay ,Middle Aged ,Quality Improvement ,Difference in differences ,Hospitalization ,Physical Therapists ,Cross-Sectional Studies ,Physical Fitness ,Physical therapy ,Medicine ,Female ,0305 other medical science ,business - Abstract
Low mobility during hospitalization remains prevalent despite associated negative consequences. The goal of this quality improvement (QI) project was to increase patient mobility and function by adding a physical therapist (PT) to an existing interprofessional care team. A mobility technician assisted treatment group patients with mobility during hospitalization based on physical therapist recommendations. Change in functional status and highest level of mobility achieved by treatment group patients was measured from admission to discharge. Observed hospital length of stay (LOS), LOS index, and 30-day all cause hospital readmission comparisons between treatment group and a comparison group on the same unit, and between cross-sectional comparison groups one year prior were used for Difference in Difference analysis. Bivariate comparisons between the treatment and a cross-sectional comparison group from one year prior showed a statistically significant change in LOS Index. No other bivariate comparisons were statistically significant. Difference in Difference methods showed no statistically significant change in observed LOS, LOS Index, or 30-day readmission. Patients in the treatment group had statistically significant improvements in functional status and highest level of mobility achieved. Physical function and mobility improved for patients who participated in mobility sessions. Mobility technicians may contribute to improved care quality and patient safety in the hospital.
- Published
- 2021
30. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans
- Author
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Andrew J. Morris, Philip A. Kern, El Khouli Rh, Zhu B, Brian S. Finlin, Esther E. Dupont-Versteegden, Patrick G. Sullivan, Hasiyet Memetimin, Zachary R. Johnson, Philip M. Westgate, Hemendra J. Vekaria, Amy L. Confides, and Chen J
- Subjects
Agonist ,medicine.medical_specialty ,β3 adrenergic receptor ,Endocrinology ,medicine.drug_class ,Chemistry ,Internal medicine ,medicine ,Glucose homeostasis ,Mirabegron ,medicine.drug - Published
- 2020
31. Acute skeletal muscle wasting and dysfunction predict physical disability at hospital discharge in patients with critical illness
- Author
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Kirby P. Mayer, Selina M Parry, Esther E. Dupont-Versteegden, Ashley Montgomery-Yates, Peter E. Morris, Melissa L. Thompson Bastin, and Amy M. Pastva
- Subjects
Male ,Weakness ,Kentucky ,Critical Care and Intensive Care Medicine ,Acute respiratory failure ,Muscle wasting ,law.invention ,Quadriceps Muscle ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,law ,Medicine ,Humans ,030212 general & internal medicine ,Longitudinal Studies ,Prospective Studies ,Leg press ,Wasting ,Aged ,Ultrasonography ,Muscle Weakness ,business.industry ,Research ,ICU-acquired weakness ,lcsh:Medical emergencies. Critical care. Intensive care. First aid ,Muscle weakness ,Skeletal muscle ,030208 emergency & critical care medicine ,lcsh:RC86-88.9 ,Length of Stay ,Middle Aged ,medicine.disease ,Intensive care unit ,Muscle atrophy ,Patient Discharge ,medicine.anatomical_structure ,Anesthesia ,Muscle power ,Physical function ,Female ,medicine.symptom ,business ,Critical illness ,Forecasting - Abstract
BackgroundPatients surviving critical illness develop muscle weakness and impairments in physical function; however, the relationship between early skeletal muscle alterations and physical function at hospital discharge remains unclear. The primary purpose of this study was to determine whether changes in muscle size, strength and power assessed in the intensive care unit (ICU) predict physical function at hospital discharge.MethodsStudy design is a single-center, prospective, observational study in patients admitted to the medicine or cardiothoracic ICU with diagnosis of sepsis or acute respiratory failure. Rectus femoris (RF) and tibialis anterior (TA) muscle ultrasound images were obtained day one of ICU admission, repeated serially and assessed for muscle cross-sectional area (CSA), layer thickness (mT) and echointensity (EI). Muscle strength, as measured by Medical Research Council-sum score, and muscle power (lower-extremity leg press) were assessed prior to ICU discharge. Physical function was assessed with performance on 5-times sit-to-stand (5STS) at hospital discharge.ResultsForty-one patients with median age of 61 years (IQR 55–68), 56% male and sequential organ failure assessment score of 8.1 ± 4.8 were enrolled. RF muscle CSA decreased significantly a median percent change of 18.5% from day 1 to 7 (F = 26.6,p = 0.0253). RF EI increased at a mean percent change of 10.5 ± 21% in the first 7 days (F = 3.28,p = 0.081). At hospital discharge 25.7% of patients (9/35) met criteria for ICU-acquired weakness. Change in RF EI in first 7 days of ICU admission and muscle power measured prior to ICU were strong predictors of ICU-AW at hospital discharge (AUC = 0.912). Muscle power at ICU discharge, age and ICU length of stay were predictive of performance on 5STS at hospital discharge.ConclusionICU-assessed muscle alterations, specifically RF EI and muscle power, are predictors of diagnosis of ICU-AW and physical function assessed by 5x-STS at hospital discharge in patients surviving critical illness.
- Published
- 2020
32. Recovery from COVID-19 and acute respiratory distress syndrome: the potential role of an intensive care unit recovery clinic: a case report
- Author
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Melissa K. Soper, Peter E. Morris, Anna G Kalema, Sherif M. Seif, Jimmi Hatton Kolpek, Ashley Montgomery-Yates, Evan Cassity, Jamie Sturgill, Kirby P. Mayer, and Esther E. Dupont-Versteegden
- Subjects
Adult ,medicine.medical_specialty ,Critical Care ,Critical Illness ,Emotional health ,medicine.medical_treatment ,Pneumonia, Viral ,Post-ICU follow-up ,lcsh:Medicine ,Case Report ,Disease ,law.invention ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,law ,Fraction of inspired oxygen ,medicine ,Humans ,030212 general & internal medicine ,Pandemics ,Mechanical ventilation ,Respiratory Distress Syndrome ,Past medical history ,Acute respiratory distress syndrome ,SARS-CoV-2 ,business.industry ,lcsh:R ,COVID-19 ,General Medicine ,Respiration, Artificial ,Intensive care unit ,Community hospital ,030228 respiratory system ,Respiratory failure ,Chronic Disease ,Emergency medicine ,Physical function ,Female ,Coronavirus Infections ,business - Abstract
Background In this case report, we describe the trajectory of recovery of a young, healthy patient diagnosed with coronavirus disease 2019 who developed acute respiratory distress syndrome. The purpose of this case report is to highlight the potential role of intensive care unit recovery or follow-up clinics for patients surviving acute hospitalization for coronavirus disease 2019. Case presentation Our patient was a 27-year-old Caucasian woman with a past medical history of asthma transferred from a community hospital to our medical intensive care unit for acute hypoxic respiratory failure due to bilateral pneumonia requiring mechanical ventilation (ratio of arterial oxygen partial pressure to fraction of inspired oxygen, 180). On day 2 of her intensive care unit admission, reverse transcription–polymerase chain reaction confirmed coronavirus disease 2019. Her clinical status gradually improved, and she was extubated on intensive care unit day 5. She had a negative test result for coronavirus disease 2019 twice with repeated reverse transcription–polymerase chain reaction before being discharged to home after 10 days in the intensive care unit. Two weeks after intensive care unit discharge, the patient returned to our outpatient intensive care unit recovery clinic. At follow-up, the patient endorsed significant fatigue and exhaustion with difficulty walking, minor issues with sleep disruption, and periods of memory loss. She scored 10/12 on the short performance physical battery, indicating good physical function. She did not have signs of anxiety, depression, or post-traumatic stress disorder through self-report questionnaires. Clinically, she was considered at low risk of developing post–intensive care syndrome, but she required follow-up services to assist in navigating the healthcare system, addressing remaining symptoms, and promoting return to her pre–coronavirus disease 2019 societal role. Conclusion We present this case report to suggest that patients surviving coronavirus disease 2019 with subsequent development of acute respiratory distress syndrome will require more intense intensive care unit recovery follow-up. Patients with a higher degree of acute illness who also have pre-existing comorbidities and those of older age who survive mechanical ventilation for coronavirus disease 2019 will require substantial post–intensive care unit care to mitigate and treat post–intensive care syndrome, promote reintegration into the community, and improve quality of life.
- Published
- 2020
33. Pioglitazone does not synergize with mirabegron to increase beige fat or further improve glucose metabolism
- Author
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Hasiyet Memetimin, Philip A. Kern, Beibei Zhu, Philip M. Westgate, Brian S. Finlin, Zachary R. Johnson, Andrew J. Morris, Amy L. Confides, Patrick G. Sullivan, Riham H. El Khouli, Hemendra J. Vekaria, Esther E. Dupont-Versteegden, and Jianzhong Chen
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Adipose tissue ,White adipose tissue ,Carbohydrate metabolism ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Brown adipose tissue ,medicine ,Glucose homeostasis ,Humans ,Hypoglycemic Agents ,Clinical Trials ,Obesity ,Glucose metabolism ,Pioglitazone ,business.industry ,Drug Synergism ,General Medicine ,Adipose Tissue, Beige ,Glucose Tolerance Test ,Middle Aged ,Thiazoles ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Glucose ,Metabolism ,Lipotoxicity ,030220 oncology & carcinogenesis ,Medicine ,Acetanilides ,Female ,Drug therapy ,Insulin Resistance ,Clinical Medicine ,Mirabegron ,business ,medicine.drug - Abstract
BACKGROUND Beige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages. METHODS We measured BAT by PET CT scans, measured beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs. RESULTS Treatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments was evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The 3 treatments also had different effects on muscle fiber type switching and capillary density. CONCLUSION The addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants. TRIAL REGISTRATION ClinicalTrials.gov NCT02919176. FUNDING NIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.
- Published
- 2020
34. Serum extracellular vesicle miR-203a-3p content is associated with skeletal muscle mass and protein turnover during disuse atrophy and regrowth
- Author
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Douglas W. Van Pelt, Esther E. Dupont-Versteegden, Ivan J. Vechetti, Marcus M. Lawrence, Benjamin F. Miller, Kathryn L. Van Pelt, Timothy A. Butterfield, and Parth Patel
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Anabolism ,Physiology ,Muscle Proteins ,Protein degradation ,Kidney ,03 medical and health sciences ,Extracellular Vesicles ,0302 clinical medicine ,Atrophy ,Internal medicine ,medicine ,Animals ,Humans ,Muscle, Skeletal ,Catabolism ,Chemistry ,Protein turnover ,Skeletal muscle ,Cell Biology ,Extracellular vesicle ,medicine.disease ,Microarray Analysis ,Muscle atrophy ,Muscular Disorders, Atrophic ,Rats ,MicroRNAs ,Muscular Atrophy ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Hindlimb Suspension ,Liver ,medicine.symptom ,030217 neurology & neurosurgery ,Biomarkers ,Research Article - Abstract
Small noncoding microRNAs (miRNAs) are important regulators of skeletal muscle size, and circulating miRNAs within extracellular vesicles (EVs) may contribute to atrophy and its associated systemic effects. The purpose of this study was to understand how muscle atrophy and regrowth alter in vivo serum EV miRNA content. We also associated changes in serum EV miRNA with protein synthesis, protein degradation, and miRNA within muscle, kidney, and liver. We subjected adult (10 mo) F344/BN rats to three conditions: weight bearing (WB), hindlimb suspension (HS) for 7 days to induce muscle atrophy, and HS for 7 days followed by 7 days of reloading (HSR). Microarray analysis of EV miRNA content showed that the overall changes in serum EV miRNA were predicted to target major anabolic, catabolic, and mechanosensitive pathways. MiR-203a-3p was the only miRNA demonstrating substantial differences in HS EVs compared with WB. There was a limited association of EV miRNA content to the corresponding miRNA content within the muscle, kidney, or liver. Stepwise linear regression demonstrated that EV miR-203a-3p was correlated with muscle mass and muscle protein synthesis and degradation across all conditions. Finally, EV miR-203a-3p expression was significantly decreased in human subjects who underwent unilateral lower limb suspension (ULLS) to induce muscle atrophy. Altogether, we show that serum EV miR-203a-3p expression is related to skeletal muscle protein turnover and atrophy. We suggest that serum EV miR-203a-3p content may be a useful biomarker and future work should investigate whether serum EV miR-203a-3p content is mechanistically linked to protein synthesis and degradation.
- Published
- 2020
35. 2023-P: Effect of Combination Therapy with a ß3 Adrenergic Receptor and PPARγ Agonist on Adipose Beiging in Obese Humans
- Author
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Zachary Johnson, Esther E. Dupont-Versteegden, Patrick G. Sullivan, Hasiyet Memetimin, Beibei Zhu, Philip M. Westgate, Hemendra J. Vekaria, Philip A. Kern, Amy L. Confides, and Brian S. Finlin
- Subjects
Agonist ,medicine.medical_specialty ,Combination therapy ,medicine.drug_class ,business.industry ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Brown adipose tissue ,Internal Medicine ,medicine ,Glucose homeostasis ,Thiazolidinedione ,Mirabegron ,business ,Pioglitazone ,medicine.drug - Abstract
Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately. We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment. Disclosure P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None. Funding National Institutes of Health (DK112282)
- Published
- 2020
36. Educational Modules of Skeletal Muscle Anatomy and Function with Models and Active Data Gathering Related to Muscular Dystrophy
- Author
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Rebecca McNall Krall, Esther E. Dupont-Versteegden, Michael P. Schultz, Robin L. Cooper, and Ann S. O’Neil
- Subjects
medicine.anatomical_structure ,business.industry ,Medicine ,Skeletal muscle ,Anatomy ,Muscular dystrophy ,business ,medicine.disease ,Function (biology) ,Active data - Published
- 2020
37. Physical Function Measured Prior to Lung Transplantation Is Associated With Posttransplant Patient Outcomes
- Author
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Carrie A. Johnson, Angela N. Henning, Esther E. Dupont-Versteegden, Alejandro G. Villasante Tezanos, Kirby P. Mayer, Kathryn M. Gaines, Evan Cassity, Maher A. Baz, Peter E. Morris, and James T. Lee
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Walk Test ,Physical function ,Cystic fibrosis ,Internal medicine ,medicine ,Hospital discharge ,Lung transplantation ,Humans ,Aged ,Retrospective Studies ,Transplantation ,business.industry ,Mortality rate ,Patient Selection ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Walking Speed ,Treatment Outcome ,Physical Fitness ,Cohort ,Body Composition ,Surgery ,Female ,business ,Lung allocation score ,Lung Transplantation - Abstract
Introduction The primary objective of this study was to determine whether pretransplant physical function is correlated with posttransplantation outcomes. Methods We performed a retrospective study of patients that participated in pretransplantation screening and subsequently underwent lung transplantation. Pretransplant variables of interest included demographics, muscle mass, body composition, physical function, and physical frailty. Correlation tests were performed to assess relationships with significance set at 0.05. Results Twenty-five patients with a mean age of 57 ± 13 years (68% male) with pretransplant lung allocation score of 45 ± 14 were included. This cohort had a 3-year mortality rate of 32% (n = 8). Pretransplant 4-m gait speed was significantly related to performance on the Short Physical Performance Battery (r = 0.74, P = .02) and distance ambulated on the 6-minute walk test (r = 0.62, P = .07) at hospital discharge. Older age was associated with slower gait speed and worse performance on sit-to-stand testing at hospital discharge (r = −0.76, P = .01 and r = −0.75, P = .01, respectively). Statistically, only diagnosis of cystic fibrosis was associated with 3-year mortality. Discussion Our study demonstrates that demographic, clinical, and physical function assessed prior to lung transplantation may be indicators of functional recovery.
- Published
- 2020
38. Muscle Power is Related to Physical Function in Patients Surviving Acute Respiratory Failure: A Prospective Observational Study
- Author
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Meghan M. Welle, Bryana G. Greenhill, Esther E. Dupont-Versteegden, Corey G. Evans, Selina M Parry, Peter E. Morris, Kirby P. Mayer, and Ashley Montgomery-Yates
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Adult ,Male ,medicine.medical_specialty ,Weakness ,medicine.medical_treatment ,Critical Illness ,030204 cardiovascular system & hematology ,Physical function ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,Internal medicine ,medicine ,Humans ,In patient ,030212 general & internal medicine ,Muscle Strength ,Prospective Studies ,Muscle, Skeletal ,Aged ,Ultrasonography ,Respiratory Distress Syndrome ,Rehabilitation ,business.industry ,Echogenicity ,General Medicine ,Middle Aged ,Intensive care unit ,Intensive Care Units ,Muscle power ,Observational study ,Female ,medicine.symptom ,business - Abstract
Background Up to 66% of patients admitted to the intensive care unit (ICU) for acute respiratory failure (ARF) develop ICU-acquired weakness, which is diagnosed by muscle strength testing. Muscle power, different from strength, is an important determinant of function that is not a common focus in patients surviving critical illness. Therefore, the purpose of this study is to assess muscle power in survivors of ARF. Methods A cross-sectional observational study performed with survivors of ARF. Muscle power, strength and physical function were assessed 4–8 weeks post-hospital discharge. Cross sectional area and echogenicity of rectus femoris and tibialis anterior muscles were assessed using ultrasonography. Healthy community-dwelling adults were included for comparison. Results 12 survivors of ARF mean age of 55.6 ± 17.1 (66% male) and 12 healthy adults mean age of 51.6.1 ± 10.3 (66% male) participated in this study. Patients in the post-ARF group had a mean muscle power of 9.9 ± 3.5 W and 63.7 ± 31.6 W for 2-lb and 10% of body-weight loads, respectively. Compared to matched controls, power in ARF group was reduced by 43%. Muscle power in post-ARF group had moderate correlations with 5-times sit-to-stand testing (r = -0.644, P = 0.024), 4-m habitual gait speed (-0.780, P = 0.002), and 6-min walk distance (r = 0.589, P = 0.044). Conclusions Muscle power is significantly reduced in survivors of critical illness and associated with deficits in physical function. These preliminary findings may support therapeutic interventions aimed at improving muscle power to potentially increase functional benefit.
- Published
- 2020
39. Massage as a mechanotherapy promotes skeletal muscle protein and ribosomal turnover but does not mitigate muscle atrophy during disuse in adult rats
- Author
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Esther E. Dupont-Versteegden, Benjamin F. Miller, Justin J. Reid, Emily R. Hunt, Douglas W. Van Pelt, Zachary R. Hettinger, Amy L. Confides, Jaime L. Laurin, Frederick F. Peelor, Timothy A. Butterfield, and Marcus M. Lawrence
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Anabolism ,Physiology ,Muscle Proteins ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Gastrocnemius muscle ,0302 clinical medicine ,Atrophy ,Internal medicine ,Rats, Inbred BN ,medicine ,Animals ,Muscle, Skeletal ,Massage ,business.industry ,Protein turnover ,Skeletal muscle ,medicine.disease ,Muscle atrophy ,Rats, Inbred F344 ,Rats ,Muscular Atrophy ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Hindlimb Suspension ,medicine.symptom ,Mechanotherapy ,business ,Ribosomes - Abstract
Aim Interventions that decrease atrophy during disuse are desperately needed to maintain muscle mass. We recently found that massage as a mechanotherapy can improve muscle regrowth following disuse atrophy. Therefore, we aimed to determine if massage has similar anabolic effects when applied during normal weight bearing conditions (WB) or during atrophy induced by hindlimb suspension (HS) in adult rats. Methods Adult (10 months) male Fischer344-Brown Norway rats underwent either hindlimb suspension (HS, n = 8) or normal WB (WB, n = 8) for 7 days. Massage was applied using cyclic compressive loading (CCL) in WB (WBM, n = 9) or HS rats (HSM, n = 9) and included four 30-minute bouts of CCL applied to gastrocnemius muscle every other day. Results Massage had no effect on any anabolic parameter measured under WB conditions (WBM). In contrast, massage during HS (HSM) stimulated protein turnover, but did not mitigate muscle atrophy. Atrophy from HS was caused by both lowered protein synthesis and higher degradation. HS and HSM had lowered total RNA compared with WB and this was the result of significantly higher ribosome degradation in HS that was attenuated in HSM, without differences in ribosomal biogenesis. Also, massage increased protein turnover in the non-massaged contralateral limb during HS. Finally, we determined that total RNA degradation primarily dictates loss of muscle ribosomal content during disuse atrophy. Conclusion We conclude that massage is an effective mechanotherapy to impact protein turnover during muscle disuse in both the massaged and non-massaged contralateral muscle, but it does not attenuate the loss of muscle mass.
- Published
- 2019
40. Cold shock protein RBM3 attenuates atrophy and induces hypertrophy in skeletal muscle
- Author
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Douglas W. Van Pelt, Amy L. Confides, Esther E. Dupont-Versteegden, Andrew Judge, and Peter W. Vanderklish
- Subjects
Male ,0301 basic medicine ,Cell type ,medicine.medical_specialty ,Physiology ,Muscle Fibers, Skeletal ,Biochemistry ,Dexamethasone ,Cell Line ,Muscle hypertrophy ,Mice ,03 medical and health sciences ,Atrophy ,Internal medicine ,medicine ,Animals ,Soleus muscle ,Chemistry ,Myogenesis ,RNA-Binding Proteins ,Skeletal muscle ,Hypertrophy ,Cell Biology ,medicine.disease ,Rats, Inbred F344 ,Muscle atrophy ,Rats ,Muscular Atrophy ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Cold Shock Proteins and Peptides ,medicine.symptom ,C2C12 - Abstract
RNA-binding motif protein 3 (RBM3), a stress-inducible RNA-binding protein that increases protein synthesis and confers cell protection in multiple cell types, has been identified as a possible regulator of skeletal muscle mass. Therefore, the primary aim of this study was to examine the impact of elevated RBM3 on skeletal muscle hypertrophy and resistance to atrophy. Plasmid-mediated overexpression of RBM3 in vitro and in vivo was used to assess the role of RBM3 in muscle. C2C12 myotubes overexpressing RBM3 were approximately 1.6 times larger than non-transfected myotubes, suggesting a role for RBM3 in hypertrophy. In addition, elevated RBM3 attenuated atrophy in myotubes exposed to dexamethasone. In agreement with in vitro results, overexpression of RBM3 in soleus muscle of F344/BN rats using electroporation techniques increased the cross sectional area of muscle fibers. Overexpression of RBM3 also attenuated muscle atrophy in rat soleus muscle undergoing disuse atrophy. These findings provide direct evidence for a novel role of RBM3 in inducing hypertrophy as well as attenuating atrophy.
- Published
- 2018
41. Enhanced skeletal muscle regrowth and remodelling in massaged and contralateral non-massaged hindlimb
- Author
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Amanda M. Hayek, Emily R. Hunt, Amy L. Confides, Sarah M. Abshire, Frederick F. Peelor, Esther E. Dupont-Versteegden, Benjamin F. Miller, Zana R. Majeed, Timothy A. Butterfield, Patrick D. Shipman, and Karyn L. Hamilton
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Anabolism ,DNA synthesis ,Physiology ,Chemistry ,Skeletal muscle ,Stimulation ,Hindlimb ,Anatomy ,medicine.disease ,Muscle atrophy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Atrophy ,medicine.anatomical_structure ,Internal medicine ,medicine ,medicine.symptom ,Myofibril ,030217 neurology & neurosurgery - Abstract
Massage, in the form of cyclic compressive loading (CCL), is associated with multiple health benefits, but its potential anabolic effect on atrophied muscle has not been investigated. We hypothesized that the mechanical activity associated with CCL induces an anabolic effect in skeletal muscle undergoing regrowth after a period of atrophy. Fisher/Brown Norway rats at 10 months of age were hind limb unloaded for a period of 2 weeks. The rats were then allowed reambulation with CCL applied at a 4.5 N load at 0.5 Hz frequency for 30 min every other day for 4 bouts during a regrowth period of 8 days. Muscle fibre cross sectional area was enhanced by 18% with massage during regrowth compared to reloading alone, and this was accompanied by elevated myofibrillar and cytosolic protein as well as DNA synthesis. Focal adhesion kinase (FAK) phosphorylation indicated that CCL increased mechanical stimulation, while a higher number of Pax7+ cells likely explains the elevated DNA synthesis. Surprisingly, the contralateral non-massaged limb exhibited a comparable 17% higher muscle fibre size compared to reloading alone, and myofibrillar protein synthesis, but not DNA synthesis, was also elevated. We conclude that massage in the form of CCL induces an anabolic response in muscles regrowing after an atrophy-inducing event. We suggest that massage can be used as an intervention to aid in the regrowth of muscle lost during immobilization. This article is protected by copyright. All rights reserved
- Published
- 2017
42. Depletion of Pax7+ satellite cells does not affect diaphragm adaptations to running in young or aged mice
- Author
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Janna R. Jackson, Angel Ho, Kevin A. Murach, Amy L. Confides, Esther E. Dupont-Versteegden, Charlotte A. Peterson, and Lina S. Ghazala
- Subjects
0301 basic medicine ,medicine.medical_specialty ,biology ,Physiology ,Cell ,Hindlimb ,Anatomy ,musculoskeletal system ,biology.organism_classification ,Diaphragm (structural system) ,Extracellular matrix ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Ageing ,Internal medicine ,Breathing ,medicine ,Satellite (biology) ,PAX7 - Abstract
Key points Satellite cell depletion does not affect diaphragm adaptations to voluntary wheel running in young or aged mice. Satellite cell depletion early in life (4 months of age) has minimal effect on diaphragm phenotype by old age (24 months). Prolonged satellite cell depletion in the diaphragm does not result in excessive extracellular matrix accumulation, in contrast to what has been reported in hind limb muscles. Up-regulation of Pax3 mRNA+ cells after satellite cell depletion in young and aged mice suggests that Pax3+ cells may compensate for a loss of Pax7+ satellite cells in the diaphragm. Future investigations should focus on the role of Pax3+ cells in the diaphragm during adaptation to exercise and ageing. Abstract Satellite cell contribution to unstressed diaphragm is higher compared to hind limb muscles, which is probably attributable to constant activation of this muscle to drive ventilation. Whether satellite cell depletion negatively impacts diaphragm quantitative and qualitative characteristics under stressed conditions in young and aged mice is unknown. We therefore challenged the diaphragm with prolonged running activity in the presence and absence of Pax7+ satellite cells in young and aged mice using an inducible Pax7CreER-R26RDTA model. Mice were vehicle (Veh, satellite cell-replete) or tamoxifen (Tam, satellite cell-depleted) treated at 4 months of age and were then allowed to run voluntarily at 6 months (young) and 22 months (aged). Age-matched, cage-dwelling, Veh- and Tam-treated mice without wheel access served as activity controls. Diaphragm muscles were analysed from young (8 months) and aged (24 months) mice. Satellite cell depletion did not alter diaphragm mean fibre cross-sectional area, fibre type distribution or extracellular matrix content in young or aged mice, regardless of running activity. Resting in vivo diaphragm function was also unaffected by satellite cell depletion. Myonuclear density was maintained in young satellite cell-depleted mice regardless of running, although it was modestly reduced in aged sedentary (–7%) and running (–19%) mice without satellite cells (P
- Published
- 2017
43. 'Muscle memory' not mediated by myonuclear number? Secondary analysis of human detraining data
- Author
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John J. McCarthy, Charlotte A. Peterson, Kevin A. Murach, Esther E. Dupont-Versteegden, and Cory M. Dungan
- Subjects
Physiology ,business.industry ,Resistance training ,Hypertrophy ,Muscle memory (strength training) ,Muscle hypertrophy ,Physiology (medical) ,Secondary analysis ,Medicine ,Humans ,Epigenetics ,business ,Muscle, Skeletal ,Neuroscience - Published
- 2019
44. Massage increases satellite cell number independent of the age‐associated alterations in sarcolemma permeability
- Author
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Sarah M. Abshire, Emily R. Hunt, Timothy A. Butterfield, Esther E. Dupont-Versteegden, and Amy L. Confides
- Subjects
Male ,medicine.medical_specialty ,Muscle Physiology ,Pax‐7 ,Cell Membrane Permeability ,Satellite Cells, Skeletal Muscle ,Membrane permeability ,IgG ,Physiology ,Immunology ,Ageing and Degeneration ,030204 cardiovascular system & hematology ,lcsh:Physiology ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Paired Box Transcription Factors ,Muscle, Skeletal ,Original Research ,sarcolemma ,satellite cells ,Massage ,Sarcolemma ,lcsh:QP1-981 ,business.industry ,Skeletal muscle ,Rats, Inbred F344 ,Rats ,Endocrinology ,medicine.anatomical_structure ,Immunoglobulin G ,Immunohistochemistry ,Cellular Physiology ,permeability ,Manual therapy ,Stem cell ,business ,030217 neurology & neurosurgery ,Intracellular - Abstract
Massage is a widely accepted manual therapy used to modulate the inflammatory response of muscle and restore function, but prolonged compression of muscle potentially causes overt injury and damage to muscle fibers. Therefore, a balance exists between the positive effects of massage and the induction of mechanical damage and injury. In addition, skeletal muscle of aged individuals displays increased stiffness, and therefore, the response to massage is likely different compared with young. We hypothesized that the aged skeletal muscle exhibits increased sarcolemmal permeability when subjected to massage compared with young skeletal muscle. Male Brown Norway/F344 rats, 10 and 30 months of age, were each divided into control, non‐massaged (n = 8) and massaged (n = 8) groups. The right gastrocnemius muscle received one bout of cyclic compressive loading for 30 min at 4.5 N as a massage‐mimetic. Muscles were dissected and frozen 24 h after massage. Alterations in sarcolemma permeability were quantified by measuring the level of intracellular IgG within the muscle fibers. Immunohistochemistry was performed to determine IgG inside fibers and Pax7+ cell number as an indicator of stem cell abundance. Average IgG intensity was not different between control and massaged animals at either age. However, a significant shift to the right of the density histogram indicated that massaged animals had more fibers with higher IgG intensity than control at 10 months. In addition, Pax7+ cell number was significantly elevated in massaged muscles compared with control at both ages. One bout of massage did not induce overt muscle injury, but facilitated membrane permeability, which was associated with an increase in satellite cell number. Data suggest that the load applied here, which was previously shown to induce immunomodulatory changes, does not induce overt muscle injury in young and old muscles but may result in muscle remodeling. Funded by NIH grant AG042699 and AT009268.
- Published
- 2019
45. Resident muscle stem cells are not required for testosterone-induced skeletal muscle hypertrophy
- Author
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Bailey D. Peck, Esther E. Dupont-Versteegden, Ally C Neal, Kevin A. Murach, Charlotte A. Peterson, Hannah A Caldwell, John J. McCarthy, and Davis A. Englund
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Satellite Cells, Skeletal Muscle ,Physiology ,Muscle Fibers, Skeletal ,Skeletal muscle hypertrophy ,Mice, Transgenic ,Biology ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Testosterone ,Cell fusion ,Rapid Report ,Stem Cells ,Skeletal muscle ,PAX7 Transcription Factor ,Cell Biology ,Hypertrophy ,musculoskeletal system ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Stem cell ,030217 neurology & neurosurgery - Abstract
It is postulated that testosterone-induced skeletal muscle hypertrophy is driven by myonuclear accretion as the result of satellite cell fusion. To directly test this hypothesis, we utilized the Pax7-DTA mouse model to deplete satellite cells in skeletal muscle followed by testosterone administration. Pax7-DTA mice (6 mo of age) were treated for 5 days with either vehicle [satellite cell replete (SC+)] or tamoxifen [satellite cell depleted (SC-)]. Following a washout period, a testosterone propionate or sham pellet was implanted for 21 days. Testosterone administration caused a significant increase in muscle fiber cross-sectional area in SC+ and SC- mice in both oxidative (soleus) and glycolytic (plantaris and extensor digitorum longus) muscles. In SC+ mice treated with testosterone, there was a significant increase in both satellite cell abundance and myonuclei that was completely absent in testosterone-treated SC- mice. These findings provide direct evidence that testosterone-induced muscle fiber hypertrophy does not require an increase in satellite cell abundance or myonuclear accretion. Listen to a podcast about this Rapid Report with senior author E. E. Dupont-Versteegden ( https://ajpcell.podbean.com/e/podcast-on-paper-that-shows-testosterone-induced-skeletal-muscle-hypertrophy-does-not-need-muscle-stem-cells /).
- Published
- 2019
46. Adipose Tissue Mast Cells Promote Human Adipose Beiging in Response to Cold
- Author
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Philip M. Westgate, Esther E. Dupont-Versteegden, Mary C. Boulanger, Brian S. Finlin, Hasiyet Memetimin, Kyle W. Taylor, Beibei Zhu, Philip A. Kern, Zachary R. Johnson, and Amy L. Confides
- Subjects
0301 basic medicine ,Male ,Chemokine ,lcsh:Medicine ,Adipose tissue ,Diseases ,Cell Count ,Cell Degranulation ,chemistry.chemical_compound ,Norepinephrine ,0302 clinical medicine ,Gene expression ,Mast Cells ,lcsh:Science ,Uncoupling Protein 1 ,2. Zero hunger ,Multidisciplinary ,Degranulation ,Endocrine system and metabolic diseases ,Thermogenesis ,Mast cell ,Cold Temperature ,medicine.anatomical_structure ,Cytokines ,Female ,Histamine ,Adult ,medicine.medical_specialty ,Subcutaneous Fat ,Biology ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Obesity ,Cell Proliferation ,Chemokine CCL26 ,Gene Expression Profiling ,lcsh:R ,nutritional and metabolic diseases ,Adipose Tissue, Beige ,In vitro ,030104 developmental biology ,Endocrinology ,chemistry ,Gene Expression Regulation ,Case-Control Studies ,biology.protein ,lcsh:Q ,Tryptases ,CCL26 ,Energy Metabolism ,030217 neurology & neurosurgery - Abstract
In a recent study, repeated cold application induced beiging in subcutaneous white adipose tissue (SC WAT) of humans independent of body mass index. To identify factors that promote or inhibit beiging, we performed multiplex analysis of gene expression with the Nanostring nCounter system (the probe set contained genes for specific immune cell markers, cytokines, and chemokines) on the SC WAT from lean subjects. Multiple correlations analysis identified mast cell tryptase and CCL26, a chemokine for mast cells, as genes whose change correlated positively with the change in UCP1 in SC WAT, leading to the hypothesis that mast cells promote SC WAT beiging in response to cold. We quantified mast cell recruitment into SC WAT and degranulation. Mast cells increased in number in SC WAT in lean subjects, and there was an increase in the number of degranulated mast cells in both lean subjects and subjects with obesity. We determined that norepinephrine stimulated mast cell degranulation and histamine release in vitro. In conclusion, cold stimulated adipose tissue mast cell recruitment in lean subjects and mast cell degranulation in SC WAT of all research participants independent of baseline body mass index, suggesting that mast cells promote adipose beiging through the release of histamine or other products.
- Published
- 2019
47. 2082-P: Pharmacological Induction of Brown and Beige Adipose Tissue
- Author
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Zachary R. Johnson, Hasiyet Memetimin, Amy L. Confides, Brian S. Finlin, Philip A. Kern, Esther E. Dupont-Versteegden, and Beibei Zhu
- Subjects
medicine.medical_specialty ,medicine.drug_class ,business.industry ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,White adipose tissue ,Thermogenin ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Brown adipose tissue ,Internal Medicine ,medicine ,Glucose homeostasis ,Thiazolidinedione ,business ,Mirabegron ,Pioglitazone ,medicine.drug - Abstract
Brown adipose tissue (BAT) is associated with improved metabolic homeostasis in humans, and studies in rodents indicate that subcutaneous white adipose tissue (SC WAT) beiging, which involves increased uncoupling protein 1 (UCP1) expression, also is associated with improved metabolism. The goal of this study was to determine the ability of mirabegron (a β3AR agonist), pioglitazone (a thiazolidinedione), or a combination of the drugs to induce brown and beige adipose tissue and to determine the effects on glucose and lipid homeostasis. We randomized obese, insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination therapy treatment groups. Euglycemic clamping, oral glucose tolerance tests, adipose tissue biopsies, and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mirabegron improved glucose homeostasis (reduced HbA1c and improved oral glucose tolerance) to a similar extent as pioglitazone without side effects or weight gain. Although mirabegron treatment increased insulin sensitivity, the effect size was much smaller than pioglitazone, yet mirabegron treatment significantly increased the insulinogenic and disposition indexes, suggesting that a major part of the mechanism of mirabegron action involved improving β-cell function. Mirabegron treatment consistently induced SC WAT beiging as evidenced by increased UCP1 expression (2.4 fold increase; P Disclosure B. Finlin: None. H. Memetimin: None. A.L. Confides: None. B. Zhu: None. Z.R. Johnson: None. E.E. Dupont-Versteegden: None. P.A. Kern: None. Funding National Institutes of Health (R01DK112282)
- Published
- 2019
48. An Educational Model for Understanding Acute Deep Tissue Injury of Motor Units: Common Lab Exercises with a New Twist
- Author
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Esther E. Dupont-Versteegden, Ashwatha Thenappan, and Robin L. Cooper
- Subjects
Educational model ,medicine.medical_specialty ,Physical medicine and rehabilitation ,Deep tissue ,medicine ,Biology ,Twist - Published
- 2019
49. Massage Protects against Disuse Atrophy in Young Adult Rats
- Author
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DW Van Pelt, Karyn L. Hamilton, Fredrick F. Peelor, Benjamin F. Miller, Amy L. Confides, Esther E. Dupont-Versteegden, Marcus M. Lawrence, Emily R. Hunt, and Timothy A. Butterfield
- Subjects
Massage ,business.industry ,medicine.medical_treatment ,Physiology ,Skeletal muscle ,Bed rest ,Biochemistry ,medicine.anatomical_structure ,Genetics ,Medicine ,Young adult ,business ,Molecular Biology ,Biotechnology ,Disuse atrophy ,Metabolic health - Abstract
Maintenance of skeletal muscle (SkM) mass is essential for maintaining mobility and metabolic health. SkM unloading or disuse, such as extended bed rest or limb immobilization, leads to rapid SkM w...
- Published
- 2019
50. Depletion of resident muscle stem cells inhibits muscle fiber hypertrophy induced by lifelong physical activity
- Author
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Davis A. Englund, Charlotte A. Peterson, Kevin A. Murach, Ivan J. Vechetti, John J. McCarthy, Esther E. Dupont-Versteegden, Cory M. Dungan, and Figueiredo Vc
- Subjects
0303 health sciences ,medicine.medical_specialty ,business.industry ,Cell ,Skeletal muscle ,Hindlimb ,medicine.disease ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,Sarcopenia ,Medicine ,Glycolysis ,Stem cell ,business ,030217 neurology & neurosurgery ,Tamoxifen ,030304 developmental biology ,medicine.drug - Abstract
BackgroundA reduction in skeletal muscle stem cell (satellite cell) content with advancing age is thought to directly contribute to the progressive loss of skeletal muscle mass and function with aging (sarcopenia). However, we reported that the depletion of satellite cells throughout adulthood did not affect the onset or degree of sarcopenia observed in sedentary old mice. The current study was designed to determine if lifelong physical activity would alter the requirements for satellite cells during aging.MethodsWe administered vehicle or tamoxifen to adult (5 months old) female Pax7-DTA mice for 5 consecutive days to effectively deplete satellite cells. Following a 2-month washout period, mice were assigned to physically active (free access to a running wheel) or sedentary (locked running wheel) conditions. Thirteen months later, at a mean age of 20 months, mice were sacrificed for subsequent analysis.ResultsSatellite cell depletion throughout adulthood negatively impacted physical function and limited muscle fiber hypertrophy in response to lifelong physical activity. To further interrogate these findings, we performed transcriptome-wide analyses on the hind limb muscles that experienced hypertrophic growth (plantaris and soleus) in response to lifelong physical activity. Our findings demonstrate that satellite cell function is muscle type-specific; fusion with fibers is apparent in oxidative muscles, while initiation of Gαi2 signaling appears to require satellite cells in glycolytic muscles to induce muscle growth..ConclusionsThese findings suggest that satellite cells, or their secretory products, are viable therapeutic targets to preserve physical function with aging and promote muscle growth in older adults who regularly engage in physical activity.
- Published
- 2019
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