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Dissertations / Theses on the topic 'Skeletal muscle'
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Foxton, Ruth. "Dysferlin in skeletal muscle and skeletal muscle disease." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268429.
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Pathare, Neeti C. "Metabolic adaptations following disuse and their impact on skeletal muscle function." [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0010024.
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Thesis (Ph.D.)--University of Florida, 2005.Typescript. Title from title page of source document. Document formatted into pages; contains 171 pages. Includes Vita. Includes bibliographical references.
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Peoples, Gregory Edward. "Skeletal muscle fatigue can omega-3 fatty acids optimise skeletal muscle function? /." Access electronically, 2004. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20041217.123607.
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Thesis (Ph.D.)--University of Wollongong, 2004.Typescript. This thesis is subject to a 12 month embargo (06/09/05 - 14/09/05) and may only be viewed and copied with the permission of the author. For further information please contact the Archivist. Includes bibliographical references: leaf 195-216.
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Salman, Mahmoud M. "Preconditioning in skeletal muscle." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1446109/.
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Ischaemia reperfusion injury of skeletal muscle is a major cause of morbidity and mortality in various surgical specialities. Developing a protective method or pharmacological agent that will limit this damage will be of considerable benefit to both patients and doctors. I have used potassium channel openers and calcium as preconditioning agents. The results show that potassium channel openers are a viable option whereas the use of calcium can exacerbate muscle damage. I looked at various protocols of ischaemic and pharmacological preconditioning. The results from both ischaemic and pharmacological preconditioning have shown a comparable decrease with some pharmacological agents in the extent of skeletal muscle infarction both in the early and late period of reperfusion. This decrease in the extent of muscle infarction is associated with changes in the levels of nitric oxide in the circulation. There was preservation of skeletal muscle oxygenation in preconditioned muscle. I have shown that preconditioning of skeletal muscle is a viable option in trying to reduce the amount of damage caused by ischaemia reperfusion injury.
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Blackwell, Danielle. "The role of Talpid3 in skeletal muscle satellite cells and skeletal muscle regeneration." Thesis, University of East Anglia, 2017. https://ueaeprints.uea.ac.uk/66948/.
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The primary cilium has recently been recognised as an essential regulator of the Sonic hedgehog (Shh) signalling pathway. Mutations that disrupt cilia function in humans can cause conditions known as ciliopathies. A wide range of phenotypes is observed in chick and mouse ciliopathy models,including polydactyly, craniofacial defects and polycystic kidneys. The Shh pathway and therefore primary cilia are vital for many developmental processes, including embryonic muscle development, with recent evidence suggesting they may also play a role in adult muscle regeneration. Our studies focus on the Talpid3 gene, which encodes a centrosomal protein required for primary cilia formation and Shh signalling. The Talpid3 loss-of-function mutant has perturbed ciliogenesis and displays many of the phenotypes that are typically associated with developmental Shh mutants and with ciliopathies. Talpid3 mutants have defects in Shh signalling, and processing of Gli transcription factors is affected in structures such as the developing limb buds and the neural tube. However, the role of Talpid3 in muscle development and regeneration remains unknown. The role of Talpid3 in adult muscle regeneration was investigated using a tamoxifen inducible, satellite cell specific knock-out of Talpid3 in mice. This mouse model was generated by crossing Talpid3 floxed mice to a mouse carrying an inducible Pax7-CreERT2 allele. To determine whether loss of Talpid3 affects muscle regeneration a cardiotoxin injury model was used. This showed that loss of Talpid3 in satellite cells results in a regeneration defect as fibres were smaller after 5, 10, 15 and 25 days of regeneration compared to control mice. This defect may be due to a reduced ability of Talpid3 mutant satellite cells to differentiate. We also show that Talpid3 plays a role in satellite cell self-renewal as we observe a complete loss of regeneration in some areas of the muscle following repeat injuries. We provide the first evidence that Talpid3 is critical for the regeneration of skeletal muscle following injury.
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Baker, Brent A. "Characterization of skeletal muscle performance and morphology following acute and chronic mechanical loading paradigms." Morgantown, W. Va. : [West Virginia University Libraries], 2007. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5325.
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Thesis (Ph. D.)--West Virginia University, 2007.Title from document title page. Document formatted into pages; contains xii, 270 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Zhang, Yan. "Cytokines and skeletal muscle wasting." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ47124.pdf.
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Oude, Vrielink Hubertus Hermanus Egbert. "Vasomotion and skeletal muscle perfusion." Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1988. http://arno.unimaas.nl/show.cgi?fid=5409.
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Walsh, Garrett Lyndon. "Skeletal muscle powered cardiac assist." Thesis, McGill University, 1988. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=63879.
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Kochamba, Gary. "Skeletal muscle powered cardiac assist." Thesis, McGill University, 1988. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61746.
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Mofarrahi, Mahroo. "Angiopoietins and skeletal muscle function." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106387.
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Angiopoietins are ligands for the endothelial cell-specific Tie-2 receptors. Angiopoietin-1 (Ang-1) activates Tie-2 receptors in the vasculature and promotes endothelial cell survival, proliferation, migration and differentiation. Angipoietin-2 (Ang-2) is synthesized mainly by endothelial cells and antagonizes Ang-1-induced Tie-2 receptor activation. In special circumstances, Ang-2 activates Tie-2 receptors and promotes angiogenesis. In this thesis, I address the regulation and functional significance of angiopoietins and Tie-2 receptors in normal and regenerating skeletal muscles. I describe first that skeletal muscle progenitor cells produce Ang-1 and Ang-2 and express Tie-2 receptors. Skeletal muscle Ang-1 and Ang-2 production increases significantly during progenitor cell differentiation to myotubes. Systemic inflammatory conditions such as severe sepsis trigger significant decline in skeletal muscle Ang-1 and Tie-2 levels while simultaneously inducing Ang-2 production through NFκB-dependent pathways. Skeletal muscle Ang-2 production is also upregulated by oxidative stress. In-vitro experiments using isolated skeletal muscle progenitors reveal that both Ang-1 and Ang-2 promote survival and differentiation of these cells but only Ang-1 induces proliferation and migration of muscle progenitors. These effects are mediated in part through phosphorylation of muscle-derived Tie-2 receptors and activation of the PI-3 kinase/AKT and ERK1/2 signaling pathways. In cardiotoxin-induced necrotic muscle injury model in mice, administration of adenoviruses expressing Ang-1 four days after the initiation of muscle injury elicits significant improvement of muscle regenerative capacity, increased angiogenesis and complete recovery of muscle contractility. These results uncover a novel and important role for Ang-1 in the promotion of skeletal muscle regeneration through enhancement of both, angiogenesis and myogenesis.Les Angiopoétines sont des ligands pour les cellules endothéliales spécifiques aux récepteurs Tie-2. L'angiopoétine-1 (Ang-1) active les récepteurs Tie-2 dans la vasculature et favorise la survie, la prolifération, la migration et la différentiation. L'Angiopoétine-2 (Ang-2) est synthétisé principalement par les cellules endothéliales et antagonise l'activation des récepteurs Tie-2 induits par Ang-1. Dans des circonstances spéciales, Ang-2 active les récepteurs Tie-2 et favorise l'angiogénèse. Dans cette thèse, j'adresse la régulation et la signification fonctionnelle des Angiopoétines et des récepteurs Tie-2 dans des muscles squelettiques normaux et en régénération. Je décris en premier que les cellules souches musculaires squelettiques produisent Ang-1 et Ang-2 et expriment les récepteurs Tie-2. La production d'Ang-1 et Ang-2 du muscle squelettique augmente de façon significative pendant la différenciation des cellules souches en myotubes. Les conditions d'inflammation systémique telle que la septicémie sévère entraîne une baisse significative des niveaux d'Ang-1 et Tie-2 dans le muscle squelettique et induit simultanément une production d'Ang-2 à travers la voie de signalisation NFκB dépendante. La production d'Ang-2 des muscles squelettiques est aussi sur-régulée par le stress oxydatif. Les expériences in-vitro qui utilisent les ascendants isolés de muscles squelettiques révèlent que ensemble Ang-1 et Ang-2 favorisent la survie, la différentiation de ces cellules mais que seulement Ang-1 induit la prolifération et la migration des muscles ascendants. Ces effets sont négociés partiellement à travers la phosphorylation des récepteurs Tie-2 dérivés de muscles et l'activation des voies de signalisation PI-3 Kinase/AKT et ERK1/2. Dans le modèle cardiotoxique nécrotique induit de muscle blessé chez la souris, l'administration d'adénovirus exprimant Ang-1 quatre jours après l'initiation du muscle blessé montre une amélioration significative de la capacité régénérative du muscle, augmentant l'angiogenèse et la récupération complète de la contractilité du muscle. Ces résultats dévoilent un nouveau et important rôle d'Ang-1 dans la promotion de la régénération du muscle squelettique à travers l'augmentation de l'angiogenèse et de la myogenèse.
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Sanderson, Alison Louise. "Regulation of skeletal muscle metabolism." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318615.
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Wang, Zai, and 王在. "Kinesin-1 in skeletal muscle." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41757877.
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Slee, Adrian. "Regulation of skeletal muscle proteolysis." Thesis, University of Nottingham, 2005. http://eprints.nottingham.ac.uk/13105/.
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Proteolysis is a component of protein turnover, controlled by multiple proteolytic systems. Alterations in system components within skeletal muscle has been associated with hypertrophy, remodelling, atrophy, apoptosis and metabolic dysregulation. Key components may have novel regulatory roles, e. g. calpain-3 and cathepsin-L. Experiments described within this thesis investigated the hypothesis that the gene expression of specific proteolytic system components within skeletal muscle may be co-ordinately regulated and altered during nutritional and pharmacological states known to modify protein turnover and induce muscle growth. Gene expression for multiple components of the calpain system was analysed in calf LD (Longissmus dorsi) by Quantitative Real-Time PCR in a plane of nutrition trial. There were three groups: low (LOW), high (HIGH) plane of nutrition and LOW to HIGH (REFED). Half of each group were slaughtered 48 hrs after refeeding, whilst the remainder were slaughtered 13 days later. Total RNA yield/g LD increased (P < 0.05) across all groups between slaughter dates. Calpain-3 expression increased in LOW and REFED and calpastatin in all groups between slaughter dates, with a trend towards significance (P = 0.073, P=0.085, respectively). In the 1St slaughter, calpain-3 expression had a trend to be lower in the LOW group and values for REFED were similar to HIGH value level. cDNA probes for unique and novel proteolytic system components were generated by RT-PCR and used to investigate the effects of acute and chronic Q-adrenergic stimulation, on the gene expression of those specific components in pig LD, by northern blotting. The ß2-adrenergic agonist clenbuterol (5 ppm) decreased glycogen levels (mg/g LD) (P < 0.001), increased cathepsin-L expression (P < 0.001) and increased E2G 1 values numerically within 24 hrs of treatment. Cathepsin-L was unchanged by adrenaline administration. Calpain-3 was unchanged with either clenbuterol or adrenaline treatment. The significance and implications of the data are discussed.
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Spencer, C. I. "Chemomechanical coupling in skeletal muscle." Thesis, Open University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383710.
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Jones, Garrett Collier. "Skeletal Muscle Recovery and Vibration." BYU ScholarsArchive, 2019. https://scholarsarchive.byu.edu/etd/8285.
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In the past decade there has been a significant increase in focus on the effect upper body vibration (UBV) has on the recovery of skeletal muscle after exercise-induced muscle damage. Recovery can be defined and investigated using a wide variety of methods. This study used three different measurements to track muscle recovery over 7 days following an exercise muscle damage protocol and applied vibration to a mathematical model. A visual analog scale (VAS) was used to measure muscle pain, a strain gauge was used to obtain maximum voluntary isometric contraction (MVIC) strength measurements, and shear wave elastography (SWE) represented muscle stiffness over the 7-day experiment. Thirty-three participants were divided into three groups. The first was a control group (C) that experienced no exercise and no therapy. The no vibration group (NV) performed the damage an exercise protocol but received no therapy. The vibration group (V) performed the same exercise protocol but also received vibration therapy. The exercise protocol consisted of 100 dumbbell curls at starting at 50% of their MVIC with one minute of rest after each set of ten. The data provided convincing evidence (27.2%, p < 0.0001) that group NV was not back to its normal stiffness after 7 days unlike group V, which was shown not to be any different from its baseline at the end of the week (9.15%, p = 0.137). Three vibration factors (����1, ����2, ����3) were added to a skeletal muscle regeneration model (SK) to simulate how vibration affects muscle regeneration. The three factors were determined by analyzing previous research to understand how vibration affects cells in the regeneration process. Adding these into SK decreased the time to recovery from about 13 days to about 7 days. Recovery was defined by reaching 10% of the original number of myofibers within the damaged muscle.
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Shue, Guay-Haur. "System models of skeletal muscle." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1058448071.
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Wang, Zai. "Kinesin-1 in skeletal muscle." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41757877.
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Stone, Michael H. "Mechanisms of Skeletal Muscle Hypertrophy." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/4532.
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Stone, Michael H. "Mechanisms of Skeletal Muscle Hypertrophy." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etsu-works/4544.
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Stone, Michael H. "Development of Skeletal Muscle Hypertrophy." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/4579.
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Dunaway, Dwayne Lee. "Nano-mechanics of skeletal muscle structures /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/8022.
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Scionti, Isabella. "Epigenetic Regulation of Skeletal Muscle Differentiation." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSEN084/document.
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LSD1 et PHF2 sont des déméthylases de lysines capables de déméthyler à la fois les protéines histones qui influencent l’expression génique et les protéines non histones en affectant leurs activités ou stabilités. Des approches fonctionnelles d’inactivation de Lsd1 ou Phf2 chez la souris ont démontré l’implication de ces enzymes dans l'engagement des cellules progénitrices au cours de la différenciation. La myogenèse est l'un des exemples les mieux caractérisés sur la façon dont les cellules progénitrices se multiplient et se différencient pour former un organe fonctionnel. Elle est initiée par une expression temporelle spécifique des gènes régulateurs cibles. Parmi ces facteurs, MYOD est un régulateur clé de l'engagement dans la différenciation des cellules progénitrices musculaires. Bien que l’action de MYOD au cours de la différenciation cellulaire ait été largement étudiée, peu de chose sont connus sur les événements de remodelage de la chromatine associés à l'activation de l'expression de MyoD. Parmi les régions régulatrices de l'expression de MyoD, la région Core Enhancer (CE) qui est transcrite en ARN activateur non codant (CEeRNA) a été démontrée pour contrôler l'initiation de l'expression de MyoD au cours de l'engagement de myoblastes dans la différenciation.Nous avons identifié LSD1 et PHF2 comme des activateurs clés du CE de MyoD. L'invalidation in vitro et in vivo de LSD1 ou l'inhibition de l'activité enzymatique de LSD1 empêche le recrutement de l'ARN PolII sur le CE, empêchant l’expression du CEeRNA. D’après nos résultats, l'expression forcée du CEeRNA restaure efficacement l'expression de MyoD et la fusion myoblastique en l'absence de LSD1. De plus, PHF2 interagit avec LSD1 en régulant sa stabilité protéique.En effet, l'ablation in vitro de PHF2 entraîne une dégradation massive de LSD1 et donc une absence d'expression du CEeRNA. Cependant, toutes les modifications d'histones qui ont lieu dans la région du CE lors de l'activation de la différenciation ne peuvent pas être directement attribuées à l'activité enzymatique de LSD1 ou PHF2. Ces résultats soulèvent la question de l'identité des partenaires de LSD1 et PHF2, qui co-participeraient à l'expression du CEeRNA et donc à l'engagement des myoblastes dans la différenciation cellulaireLSD1 and PHF2 are lysine de-methylases that can de-methylate both histone proteins, influencing gene expression and non-histone proteins, affecting their activity or stability. Functional approaches using Lsd1 or Phf2 inactivation in mouse have demonstrated the involvement of these enzymes in the engagement of progenitor cells into differentiation. One of the best-characterized examples of how progenitor cells multiply and differentiate to form functional organ is myogenesis. It is initiated by the specific timing expression of the specific regulatory genes; among these factors, MYOD is a key regulator of the engagement into differentiation of muscle progenitor cells. Although the action of MYOD during muscle differentiation has been extensively studied, still little is known about the chromatin remodeling events associated with the activation of MyoD expression. Among the regulatory regions of MyoD expression, the Core Enhancer region (CE), which transcribes for a non-coding enhancer RNA (CEeRNA), has been demonstrated to control the initiation of MyoD expression during myoblast commitment. We identified LSD1 and PHF2 as key activators of the MyoD CE. In vitro and in vivo ablation of LSD1 or inhibition of LSD1 enzymatic activity impaired the recruitment of RNA PolII on the CE, resulting in a failed expression of the CEeRNA. According to our results, forced expression of the CEeRNA efficiently rescue MyoD expression and myoblast fusion in the absence of LSD1. Moreover PHF2 interacts with LSD1 regulating its protein stability. Indeed in vitro ablation of PHF2 results in a massive LSD1 degradation and thus absence of CEeRNA expression. However, all the histone modifications occurring on the CE region upon activation cannot be directly attributed to LSD1 or PHF2 enzymatic activity. These results raise the question of the identity of LSD1 and PHF2 partners, which co-participate to CEeRNA expression and thus to the engagement of myoblast cells into differentiation
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Yeung, Wai Ella, and 楊慧. "Eccentric contraction-induced injury in mammalian skeletal muscle." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29750313.
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Pillitteri, Paul J. "Regeneration of Rat Skeletal Muscle Following a Muscle Biopsy." Ohio University / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1118087917.
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Arc-Chagnaud, Coralie. "Regulation of antioxidant defenses in the prevention of skeletal muscle deconditioning." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONT4005.
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Le système musculaire joue un rôle primordial dans l’homéostasie de l’organisme. Il est impliqué dans différentes fonctions indispensables aux activités de la vie quotidienne telles que la production de mouvement, la locomotion, le maintien postural et l’équilibre. La qualité du tissu musculaire est donc primordiale dans le maintien de la qualité de vie et, à long terme, à la longévité. L'hypoactivité et le vieillissement sont deux situations qui entraînent le déconditionnement musculaire, et qui partagent une caractéristique commune: une perte de force musculaire, une atrophie et la modification du typage musculaire, ainsi que l'accumulation de tissu adipeux intramusculaire. Aujourd'hui, il existe de nombreuses données dans la littérature indiquant un lien entre le stress oxydant et le déconditionnement musculaire. Le but de cette thèse était d'évaluer l'impact de la modulation des défenses antioxydantes sur la prévention du déconditionnement musculaire. Cela a été étudié sous deux angles, l'un dans le contexte du vieillissement, et le second dans un contexte d'hypoactivité. La première étude avait pour but d'évaluer la fragilité chez un modèle souris âgées, utilisant un groupe de souris WT et un groupe de souris transgéniques sur-exprimant l'enzyme G6PD. Nous avons évalué des paramètres de qualité musculaire et de stress oxydant et avons réalisé une analyse transcriptomique à partir d'échantillons musculaires des souris de chacun des deux groupes. La seconde étude a été conduite dans le but d'évaluer les effets d'un cocktail enrichi en composés anti-oxydants et anti-inflammatoires, durant deux mois d'hypoactivité (modèle Bedrest). Nos résultats ont démontré l’inefficacité de cette supplémentation sur la prévention de la perte de masse et de force musculaire. De plus, les données concernant les mécanismes moléculaires ont démontré une altération des processus de récupération chez les sujets supplémentés.Les conclusions de nos études donnent des pistes sur les stratégies anti-oxydantes les plus appropriées contre le déconditionnement musculaire. Il semble préférable de intéresser à la stimulation des systèmes de défenses endogènes, plutôt que de se centrer sur une supplémentation nutritionnelle exogène. Néanmoins, la complexité des voies de signalisation redox requièrent une meilleure compréhension pour optimiser les mesures de prévention afin de limiter la perte de fonction musculaireMusculoskeletal system plays a key role in organism’s well-functioning and is responsible for a large variety of functions such as posture, locomotion, balance, and activities of daily life. The quality of the skeletal muscle is therefore capital to maintain quality of life and, in the long term, survival. Hypoactivity and aging are two situations that cause skeletal muscle deconditioning, therefore sharing common characteristics: loss of muscle strength, muscular atrophy and MyHC redistribution, as well as IMAT accumulation. To date, there is plenty of evidence supporting a causative link between oxidative stress phenomenon and muscle deconditioning.The general aim of this PhD thesis was to evaluate the impact of the modulation of the antioxidant defenses on the prevention of muscle deconditioning. It has been studied from two perspectives, the first one in the context of aging and the second in the context of hypoactivity.The first study aimed to evaluate frailty in old female animals, using WT and G6PD-overexpressing mice. We evaluated muscle quality parameters and oxidative stress markers. Finally, we performed a transcriptomic analysis of muscle samples and highlighted differentially expressed genes in both groups of mice.The second study was conducted to evaluate the effects of a cocktail enriched in antioxidant/anti-inflammatory molecules in a 2-month hypoactivity experiment (Bedrest model). Our results clearly demonstrate the ineffectiveness of this type of supplementation in the prevention of muscle mass and strength loss. Moreover, data regarding muscle molecular mechanisms highlight an alteration of recovery processes in the supplemented subjects.Finally, the conclusions of our two studies gave clues on the suitable antioxidant modulation strategy for the prevention of skeletal muscle deconditioning. It seems preferable to focus on the stimulation of endogenous defense system whether than towards exogenous supply of nutritional antioxidants. Nevertheless, the complexity of redox signaling requires better understanding to optimize countermeasures in muscle wasting situations
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Wood, Stephanie Ann Cardinal Trevor R. "A morphological and hemodynamic analysis of skeletal muscle vasculature : a thesis /." [San Luis Obispo, Calif. : California Polytechnic State University], 2008. http://digitalcommons.calpoly.edu/theses/16/.
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Thesis (M.S.)--California Polytechnic State University, 2008."July 2008." "In partial fulfillment of the requirements for the degree [of] Master of Science in Engineering with a specialization in Biomedical Engineering." "Presented to the faculty of California Polytechnic State University, San Luis Obispo." Major professor: Trevor Cardinal, Ph.D. Includes bibliographical references (leaves 96-101). Also available on microfiche and online.
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Aydin, Jan. "Skeletal muscle calcium homeostasis during fatigue : modulation by kinases and mitochondria /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-247-7/.
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Vlahovich, Nicole. "The role of cytoskeletal tropomyosins in skeletal muscle and muscle disease." Thesis, View thesis, 2007. http://handle.uws.edu.au:8081/1959.7/32176.
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Cells contain an elaborate cytoskeleton which plays a major role in a variety of cellular functions including: maintenance of cell shape and dimension, providing mechanical strength, cell motility, cytokinesis during mitosis and meiosis and intracellular transport. The cell cytoskeleton is made up of three types of protein filaments: the microtubules, the intermediate filaments and the actin cytoskeleton. These components interact with each other to allow the cell to function correctly. When functioning incorrectly, disruptions to many cellular pathway have been observed with mutations in various cytoskeletal proteins causing an assortment of human disease phenotypes. Characterization of these filament systems in different cell types is essential to the understanding of basic cellular processes and disease causation. The studies in this thesis are concerned with examining specific cytoskeletal tropomyosin-defined actin filament systems in skeletal muscle. The diversity of the actin filament system relies, in part, on the family of actin binding proteins, the tropomyosins (Tms). There are in excess of forty Tm isoforms found in mammals which are derived from four genes: α, β, γ and δTm. The role of the musclespecific Tms in striated muscle is well understood, with sarcomeric Tm isoforms functioning as part of the thin filament where it regulates actin-myosin interactions and hence muscle contraction. However, relatively little known about the roles of the many
cytoskeletal Tm isoforms. Cytoskeletal Tms have been shown to compartmentalise to form functionally distinct filaments in a range of cell types including neurons (Bryce et al., 2003), fibroblasts (Percival et al., 2000) and epithelial cells (Dalby-Payne et al., 2003). Recently it has been shown that cytoskeletal Tm, Tm5NM1 defines a cytoskeletal structure in skeletal muscle called the Z-line associated cytoskeleton (Z-LAC) (Kee et al., 2004).The disruption of this structure by over-expression of an exogenous Tm in transgenic mice results in a muscular dystrophy phenotype, indicating that the Z-LAC plays an important role in maintenance of muscle structure (Kee et al., 2004). In this study, specific cytoskeletal Tms are further investigated in the context of skeletal muscle. Here, we examine the expression, localisation and potential function of cytoskeletal Tm isoforms, focussing on Tm4 (derived from the δ- gene) and Tm5NM1 (derived from the γ-gene). By western blotting and immuno-staining mouse skeletal muscle, we show that cytoskeletal Tms are expressed in a range of muscles and define separate populations of filaments. These filaments are found in association with a number of muscle structures including the myotendinous junction, neuromuscular junction, the sarcolemma, the t-tubules and the sarcoplasmic reticulum. Of particular interest, Tm4 and Tm5NM1 define cytoskeletal elements in association with the
saroplasmic reticulum and T-tubules, respectively, with a separation of less than 90 nm between distinct filamentous populations. The segregation of Tm isoforms indicates a role for Tms in the specification of actin filament function at these cellular regions. Examination of muscle during development, regeneration and disease revealed that Tm4 defines a novel cytoskeletal filament system that is orientated perpendicular to the sarcomeric apparatus. Tm4 is up-regulated in both muscular dystrophy and nemaline myopathy and also during induced regeneration and focal repair in mouse muscle. Transition of the Tm4-defined filaments from a predominsnatly longitudinal to a predominantly Z-LAC orientation is observed during the course of muscle regeneration. This study shows that Tm4 is a marker of regeneration and repair, in response to disease, injury and stress in skeletal muscle.
Analysis of Tm5NM1 over-expressing (Tm5/52) and null (9d89) mice revealed that compensation between Tm genes does not occur in skeletal muscle. We found that the levels of cytoskeletal Tms derived from the δ-gene are not altered to compensate for the loss or gain of Tm5NM1 and that the localisation of Tm4 is unchanged in skeletal muscle of these mice. Also, excess Tm5NM1 is sorted correctly, localising to the ZLAC. This data correlates with evidence from previous investigations which indicates that Tm isoforms are not redundant and are functionally distinct (Gunning et al., 2005). Transgenic and null mice have also allowed the further elucidation of cytoskeletal Tm function in skeletal muscle. Analyses of these mice suggest a role for Tm5NM1 in glucose regulation in both skeletal muscle and adipose tissue. Tm5NM1 is found to colocalise with members of the glucose transport p fibres and analysis of both transgenic and null mice has shown an alteration to glucose uptake in adipose tissue. Taken together these data indicate that Tm5NM1 may play a role in the translocation of the glucose transport molecule GLUT4. In addition to this Tm5NM1 may play a role in adipose tissue regulation, since over-expressing mice found to have increased white adipose tissue and an up-regulation of a transcriptional regulator of fat-cell formation,
PPAR-γ.
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Maenhout, Mascha. "Strain fields within contracting skeletal muscle." Eindhoven : Maastricht : Technische Universiteit Eindhoven ; University Library, Maastricht University [Host], 2002. http://arno.unimaas.nl/show.cgi?fid=7018.
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Geukes, Foppen Remco Jan. "Electrical bistability of skeletal muscle membrane." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2005. http://dare.uva.nl/document/78574.
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Raue, Ulrika. "Skeletal muscle gene expression with age." Virtual Press, 2007. http://liblink.bsu.edu/uhtbin/catkey/1370882.
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The aim of this research was to investigate myogenic (i.e. growth) and proteolytic (i.e. breakdown) gene expression (GE) in skeletal muscle of young and old women. Myogenic (MyoD, MRF4, Myf5, myogenin, myostatin) and proteolytic (Atrogin-1, MuRF-1, FOXO3A) genes were examined in the basal state and after resistance exercise (RE). Six old women (OW: 85 ± 1 y) and eight young women (YW: 23 ± 1) performed 3 x 10 knee extensions at 70% of 1-repetition-maximum. Muscle biopsies were obtained from the vastus lateralis (i.e. thigh) before and 4 hours after RE.In the basal state, OW expressed higher levels (p<0.05) of MyoD, MRF4, myf5, myogenin, myostatin, FOXO3A and MuRF-1 compared to YW. Fiber type specific GE analysis in the OW showed that slow-twitch muscle fibers (MHC I) expressed higher levels (p<0.05) of myogenin and Atrogin-1, compared to fast-twitch (MHC Ila) fibers. In response to RE both YW and OW increased (p<0.05) mRNA levels of MyoD and MRF4, while a decrease (p<0.05) was observed for myostatin. MuRF-1 mRNA increased (p<0.05) in both age groups, while there was an age-specific induction (p<0.05) of Atrogin-1 after RE. Fiber type specific GE after RE in the old women showed that MHC Ila fibers did not induce myogenic GE. Robust increases (p<0.05) in MyoD, MRF4, and myogenin were only observed in the MHC I fibers. Both fiber types decreased (p<0.05) myostatin, and increased Atrogin-1 with RE. MuRF-1 mRNA levels increased specifically in MHC Ila fibers. In summary, skeletal muscle of OW expresses higher levels of mRNA for most selected genes at rest. With RE, aging skeletal muscle retains the ability to induce myogenic GE, although exclusive to MHC I fibers. After RE, proteolytic GE induction is greater in OW and most pronounced in MHC Ila fibers. Collectively, these data suggest that an imbalance exists in the regulation of the myogenic and proteolytic program in aging skeletal muscle. This research also provides the first evidence of intrinsic molecular differences between MHC I and MHC Ila fibers in OW, and may, in part, explain the MHC Ila atrophy apparent in sarcopenic muscle.School of Physical Education, Sport, and Exercise Science
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Tallon, Mark J. "Carnosine metabolism in human skeletal muscle." Thesis, University of Chichester, 2005. http://eprints.chi.ac.uk/843/.
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Kwende, Martin M. N. "The biomechanics of skeletal muscle ventricles." Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283451.
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Levy, Louis Bernard. "Nutrition, infection and skeletal muscle function." Thesis, University of Southampton, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316459.
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Campbell, Robert N. "Glucose-regulated transcription in skeletal muscle." Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427295.
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Alam, Nasreen. "Malonyl-coa metabolism in skeletal muscle." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300485.
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Smith, N. "Thiol signalling in skeletal muscle ageing." Thesis, University of Liverpool, 2018. http://livrepository.liverpool.ac.uk/3026986/.
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An age-related loss of muscle mass is associated with increased frailty in the elderly. The effect is felt at both a national scale, with an increased budgetary demand for health services directed towards the ageing population, and by the individual where reduced mobility significantly reduces their quality of life. It is unclear whether all skeletal muscle types are affected in the same manner. This thesis considered how thiol signalling, facilitated through reactive thiol groups on cysteine amino acids, may affect skeletal muscle ageing as it is crucial for normal intracellular function. Several studies have identified reactive oxygen species (ROS) as crucial signalling molecules in healthy muscle and various proteins can detect and respond to changes in their concentration. The cysteines are evolutionarily conserved in functionally important locations and have a direct impact on protein function, affecting either its active site or conformation. In healthy muscle, proteins can quickly and efficiently respond to changes in ROS concentrations via this mechanism whereas in aged muscle these responses appear to be impaired. The quadriceps and soleus muscles were selected because of their differing primary metabolic pathways and physiology, reflecting fast and slow twitch muscle respectively. This enabled determination of age related changes to the redox proteome between two different skeletal muscles. They are hypothesised to age differently and to determine this, adult (12 months) and old (24 months) tissue were subjected to a deep proteomics investigation, elucidating changes to the global proteome of ageing mouse muscle as well as using differential labelling of reduced and reversibly oxidised cysteine residues to identify redox-susceptible locations on individual proteins. Prior to this a proteomics study had not analysed changes to the redox proteome between two skeletal muscle tissues before. Analysis of the quadriceps label free results identified changes to redox protein abundance such as a significant increase in Protein Disulphide Isomerase, crucial to disulphide bond formation and breakage. HSC70, important for protein folding, was significantly decreased with age. Differential labelling of specific cysteine residues demonstrated Cys46 increased in its reduced form with age in PARK7. Furthermore, many changes observed in the label free analysis highlighted cytoskeletal proteins as those primarily affected. The soleus label free results demonstrated significant decreases in abundance of a number of mitochondrial proteins involved in the electron transport chain such as NAD(P)H dehydrogenase and ATP Synthase. One example of differential labelling highlighted ATP Synthase Cys101 as becoming increasingly reduced with age. This increase in a reduced redox state of cysteines was observed across a range of other mitochondrial proteins, possibly indicating a negative impact on energy metabolism in the soleus with age. A successful preliminary study considered the effect of stretching C2C12 mouse skeletal muscle cells in vitro. A protocol for testing the effect of mechanical stretching on C2C12 cells was optimised with a future goal of producing replicable in vitro proteomics data and thereby reducing the requirement for animal tissue. The studies in this thesis identified various redox proteome changes in quadriceps and soleus muscle with age. This data will provide a basis for a targeted analysis of musculoskeletal proteins with a view to a better understanding of musculoskeletal ageing and its impact via the proteome.
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Stickland, Neil Charles. "Development and growth of skeletal muscle." Thesis, University of Edinburgh, 1998. http://hdl.handle.net/1842/30012.
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The main body of this work contributes to an understanding of the development and growth of skeletal muscle in a range of Vertebrates from fish to pigs. Particular emphasis is paid to the contribution of numbers and types of muscle fibres to overall muscle growth and ultimate mass, and also to the mechanisms whereby factors such as nutrition in mammals and temperature in fish may affect these parameters. The work is divided into three main sections. The first section covers aspects of prenatal mammalian development including myogenesis and placentation. Muscle develops as two populations of muscle fibres. Primary myofibres form first and this is followed by the formation of a larger populations of secondary fibres. Restricting maternal nutrition may compromise the formation of secondary fibres but not primaries. Studies on the placenta and on levels of specific factors, e.g. insulin-like growth factors, has given some insight into the mechanism of nutritional effects on muscle fibre development. Nutritional experiments have highlighted energy levels in the earlier stages of gestation as most critical in the development of muscle fibre number. This finding has been developed in pig experiments which have shown that extra feed in early gestation can produce piglets with more secondary fibres at birth and which grow faster and more efficiently to slaughter. The second section incorporates work on postnatal mammalian muscle. Studies, on pigs in particular, have shown that primary fibre number relates more to genotype that does secondary fibre number. Total muscle fibre number correlates with some parameters of carcass leanness and with postnatal growth rate and feed conversion efficiency. The influence of factors such as nutrition, dwarfism, obesity and sex on aspects of muscle growth and muscle fibre types has been studied as well as the functional adaptation of muscle metabolism in different species. The third section includes work on fish muscle development and growth in a range of species.
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Nikoi, Naa-Dei. "Cellulose nanowhiskers for skeletal muscle engineering." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/cellulose-nanowhiskers-for-skeletal-muscle-engineering(30db0446-d55b-40aa-b759-c8e2c71a4cf6).html.
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Prior work has shown that spin-coating tunicin cellulose nanowhiskers onto a glass surface creates a highly oriented surface that supports the adhesion, spreading and proliferation of myotubes. Building on this work, this project aimed to develop culture surfaces with biologically active topography and tuneable stiffness with the aim of better mimicking native muscle tissue. The ultimate aim is to develop biomaterials that can direct the differentiation of mesenchymal stem cells. Cellulose nanocrystals (CNWs) from Ascidiella spp were isolated and characterised. Polyelectrolyte multilayers (PEMs) are nanocomposite films formed from the sequential deposition of oppositely charged polymers and offer a flexible method of building films with a variety of chemical compositions and physical properties. CNWs were used in combination with chitosan to create PEMs using a combination of two well-established, low-cost and facile production methods, dip-coating and spin-coating. The resulting PEM was shown to be a nanoporous substrate that was stable under cell culture conditions. It robustly allowed the attachment, alignment and myogenic differentiation of the immortalised C2C12 myoblast cell line. Proteomic analysis of the ECM produced by C2C12 cells in response to the substrate showed that cells cultured on CNW-chitosan PEMs secreted increased fibronectin, tenascin-c, elastins and collagen I, an expression pattern that is consistent with a more developmental, rather than mature, muscle ECM. The thickness and mechanical stiffness of the PEM films could be tuned by replacing replacing increasing volume fractions of CNWs with poly(4-sodium styrene sulfonate) (PSS). The thickness of the dry films increased with increasing CNW content, increasing from 20 nm for films containing 12 bilayers of PSS and chitosan to 100 nm for films containing 12 bilayers of CNW and chitosan. The compressive stiffness of hydrated films decreased with increasing CNW content, from 1.67 ± 0.73 MPa, to 1.06 ± 0.24 MPa. Unfortunately, PSS-modified PEMs proved to be cytotoxic to cells. The response of bone marrow stem cells to the substrates showed that mesenchymal stem cells were contact guided by the CNWs, but did so by avoiding the material, thus being better guided by substrates where CNWs were present at a low surface density than substrates where it was present at a high density. When cultured directly on PEMs, MSCs expressed myogenin, a key marker of terminal muscle differentiation, which was suggestive, but not definitive, of a potential of the biomaterial to direct the myogenic differentiation of MSCs.
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Wilson, Emma. "Force response of locust skeletal muscle." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/190857/.
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The force response of the locust hind leg extensor muscle to input excitation pulses is modelled. Despite the processes behind muscle contraction being well established, no broadly valid method of modelling skeletal muscle exists. Studies that compare the merits of existing models are extremely scarce and researchers make various assumptions in order to simplify the complex, nonlinear behaviour of the muscle. Locusts provide an opportunity to develop a muscle model in a simpler system, that will still show similar properties to that of mammalian muscles. In developing a model previous work is considered, and complexity is introduced in the experimental conditions in stages. This meant a model could be built up in parts. This approach reduces the need for questionably valid assumptions. The main focus of this work is modelling activated isometric muscle. Experimental data was collected by stimulating the extensor muscle and measuring the force generated at the tibia. In the first instance the response to individual stimulus pulses is modelled. This is extended to develop a predictive model capable of estimating the isometric force response to general pulse train inputs. In developing the model, data was fit to existing models, and from this an improved isometric model developed. The effect of changing the isometric muscle length is considered. Commonly changing the muscle length is assumed to just scale the force response. This assumption is poor. The dynamics of the force response were found to be modifed by the change in muscle length, and the isometric model adapted to include this dependency. Results related to the non-isometric behaviour are also presented. Passive muscle is usually just modelled over the lengthening period, however, the whole stretch-shorten cycle is considered here. A model, adapted from the standard linear model, is developed to describe the passive force response.
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Metzger, Sabrina Kinzie. "Modeling of excitation in skeletal muscle." Wright State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=wright1620983611677044.
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England, Eric M. "Postmortem metabolism in porcine skeletal muscle." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/54580.
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Once an animal is harvested for meat, skeletal muscle attempts to maintain ATP at or near antemortem levels. To maintain ATP levels postmortem, stored glycogen is catabolized to produce ATP through glycolysis and possibly oxidative metabolism. Hydrolysis of the produced ATP acidifies muscle until an ultimate pH is reached. The ultimate pH of meat directly impacts the quality characteristics of color, texture, and water holding capacity. Therefore, our research intends to describe the contributions glycolysis and oxidative metabolism play in determining ultimate pH and fresh meat quality. Traditionally, glycogen content at death was thought to be responsible for dictating ultimate pH. This was especially true in oxidative muscle with limited glycogen stores. Yet, our research indicated that in the presence of excess glycogen, oxidative muscle maintains a high ultimate pH. Rather, pH inactivation of phosphofructokinase is responsible for terminating postmortem glycolysis and brackets ultimate pH between 5.9 – 5.5. Meat with a pH below this range is uncommon. However, AMPK γ3R200Q mutant pigs produce meat with an ultimate pH near 5.3. Due to lower AMP deaminase abundance in their muscle, AMP levels are elevated late postmortem. Because AMP is a potent activator of phosphofructokinase, the aberrant meat quality from AMPK γ3R200Q mutant pigs is caused by extended postmortem glycolysis. Combined, these data further our understanding of the factors that contribute to the formation of fresh meat quality.
We also characterized AMPK γ3R200Q muscle by investigating antemortem skeletal muscle lactate transport. Lactate is transported in or out of tissues by proton-linked iii monocarboxylate transporters (MCTs). Previous reports indicated that acute activation of AMPK increased monocarboxylate transporter expression in skeletal muscle of other species. Yet, it was unknown the impact chronic activation of AMPK will have on MCT1, MCT2, and MCT4 expression in pigs. Compared to wild-type pigs, the longissimus lumborum of AMPK γ3R200Q pigs increased both MCT2 and MCT4 protein expression. Our data suggest glycolytic skeletal muscle from the AMPK γ3R200Q pigs has increased capacity for antemortem lactate export from muscle and possibly increased pyruvate transport into the mitochondria.Ph. D.
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Myhal, Mark. "Skeletal muscle, age, overload, and oxandrolone/." The Ohio State University, 1999. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488190109868676.
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Johnston, Nicholas Ian Falkinder. "Arginine vasopressin in foetal skeletal muscle." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/22358.
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Arginine vasopressin (AVP) is also known as anti-diuretic hormone (ADH). The two major effects of this peptide, that of increasing blood pressure by vasoconstriction and reducing water loss by promoting water re-absorption in the kidney, are described as its primary functions. But other effects of AVP have been demonstrated. For example, in the adult mammal AVP has a role in platelet aggregation, hepatic glycogenloysis, and memory consolidation, and the purpose of the course of study described in this thesis was to examination a putative alternative function for AVP. In certain rat myogenic cell lines introduction of vasopressin results in promotion of fusion and up-regulation of muscle specific gene expression. This effect has been described as being mediated by the V1a-vascular receptor. In addition, Data were published suggesting there was a significant amount of AVP immunoreactivity (ir-AVP) in human foetal skeletal muscle. ir-AVP was described at concentrations that could not be explained by plasma concentration, and described in relation to gestation age. Taken together these results suggest a significant role for vasopressin in skeletal muscle for development, and point to an additional alternative site for the synthesis of biologically active AVP. An extraction method was developed which employed solid phase extraction (SPE) followed by radioimmunoassay. The physical recovery of the SPE stage was reproducibly better than 70% when extracting AVP from homogenised muscle tissues. The radioimmunoassay had a cross reactivity of less than 0.01% with both oxytocin and arginine vasotocin. This extraction method was developed as a response to the demonstration that the direct assay of acidified extracts did not supply an accurate measure of the amount of vasopressin in extracted muscle. The reported ir-AVP was shown to probably be the result of acid inference in the assay. Levels of ir-AVP from foetal muscle samples extracted using SPE were not significant. This was in contrast to levels found in several positive control tissues - human foetal adrenal and pituitary glands, and rat adult adrenal glands - that were in close agreement with previously published data.
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Fry, William Mark. "K+ channels in Xenopus skeletal muscle /." St. John's NF : [s.n.], 2001.
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Needham, Elise. "Personalised phosphoproteomics of skeletal muscle metabolism." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/28191.
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Protein phosphorylation dynamically integrates environmental and intracellular information to control virtually all biological processes. Challenges in determining the upstream regulation and downstream effects of phosphorylation obscures our functional understanding of cellular communication. In this thesis, I developed approaches to contextualise and prioritise phosphorylation events, focusing on the dynamic regulation of skeletal muscle metabolism by insulin and exercise. I measured phosphoproteomes of an in vitro panel of exercise-like stimuli to dissect upstream influences on exercise signalling. My integrative analysis with acute exercise phosphoproteomes revealed that emergent outcomes like protein secretion require concurrent kinase activation by distinct stimuli. To address the challenge of prioritising phosphosites with downstream functions most crucial to a biological phenomenon, I developed personalised phosphoproteomics. This experimental and computational framework identifies functionally enriched signalling by utilising human biological variance. To employ this method, I performed two independent phosphoproteomics studies investigating how exercise potentiates insulin sensitivity and how insulin resistance impacts metabolism in human skeletal muscle. My approach identified signalling on both known and previously unidentified sites on proteins intimately involved in glucose metabolism. This included a new co-operative relationship between mTOR and AMPK, for which I found a role in metabolic regulation. Collectively, these studies delineated skeletal muscle signalling responses and established personalised phosphoproteomics as a general approach to investigate the signal transduction underlying complex biology.
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Ebert, Scott Matthew. "Molecular mechanisms of skeletal muscle atrophy." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/4967.
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Skeletal muscle atrophy is a common and often debilitating complication of diverse stresses including muscle disuse, fasting, aging, critical illness and many chronic illnesses. However, the pathogenesis of muscle atrophy is still poorly understood. The thesis herein describes my studies investigating the molecular mechanisms of skeletal muscle atrophy. Using mouse skeletal muscle and cultured skeletal myotubes as experimental systems, I discovered a novel stress-induced pathway in skeletal muscle that causes muscle atrophy.
The pathway begins with stress-induced expression of ATF4, a basic leucine zipper (bZIP) transcription factor with an evolutionarily ancient role in cellular stress responses. I found that diverse stresses including fasting and muscle disuse increase expression of ATF4 in skeletal muscle. ATF4 then activates the growth arrest and DNA damage-inducible 45a (Gadd45a) gene, leading to increased expression of Gadd45a protein, an essential and inducible subunit of DNA demethylase complexes. Gadd45a localizes to skeletal myonuclei where it interacts with and stimulates demethylation of a specific region in the promoter of the cyclin dependent kinase inhibitor 1a (Cdkn1a) gene. By demethylating the Cdkn1a promoter, Gadd45a activates the Cdkn1a gene, leading to increased expression of Cdkn1a protein, also known as p21WAF1/CIP1. Cdkn1a stimulates protein breakdown (a critical pro-atrophy process) and inhibits anabolic signaling, protein synthesis and PGC-1α expression (processes that maintain healthy skeletal muscle and protect against atrophy). As a result, Cdkn1a causes skeletal muscle fibers to undergo atrophy.
Importantly, interventions that reduce any one component of this pathway (ATF4, Gadd45a or Cdkn1a) reduce skeletal muscle atrophy during fasting, muscle disuse, and perhaps other skeletal muscle stresses such as illness and aging. Conversely, forced expression of any one component of this pathway is sufficient to cause skeletal muscle fiber atrophy in the absence of upstream stress. These data suggest the ATF4/Gadd45a/Cdkn1a pathway as a potential therapeutic target.
Collectively, my studies demonstrate that the sequential, stress-induced expression of ATF4, Gadd45a and Cdkn1a is a critical process in the pathogenesis of skeletal muscle atrophy. This significantly advances our understanding of how muscle atrophy occurs and it opens up new avenues of investigation into the causes and treatment of muscle atrophy.
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Simmers, Jessica L. "nNos localization, muscle function and atrophy in skeletal muscle disorders." Thesis, The Johns Hopkins University, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3573097.
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In skeletal muscle, loss of neuronal nitric oxide synthase (nNOS) from the sarcolemma has been observed in a few muscular dystrophies and myopathies. However, the extent of this phenomenon, its mechanism, and its physiological impact are not well understood. Using immunofluorescent staining for nNOS, a survey of 161 patient biopsies found absent or reduced sarcolemmal nNOS in 43% of patients. Patient mobility and muscle functional status correlated with nNOS mislocalization from the sarcolemma. Mouse models of inherited and acquired myopathies showed similar loss of sarcolemmal nNOS and impaired mobility and muscle function. A proteomic approach, using mass spectrometry and differentially labeled control and steroid-induced myopathy (SIM) mouse samples, found novel nNOS binding proteins including alpha-actinin-3 (ACTN3), which exhibited decreased interaction with nNOS after steroid treatment. It revealed a potential explanation for impaired muscle function in SIM as nNOS interactions were lost at the sarcomere and gained at the sarcoplasmic reticulum impairing contractility. Treating nNOS-deficient mice with steroids demonstrated that loss of sarcolemmal nNOS reduces muscle contractility and strength in SIM through increased nitric oxide (NO) signaling. In SIM mice treated with a nitric oxide donor and steroids, nitric oxide partially protects the muscle from atrophy and improves muscle fatigability and recovery suggesting nNOS mislocalization also decreases NO availability. These findings show that loss of sarcolemmal nNOS is a common phenomenon that negatively impacts muscle function. Therapeutic strategies targeting nNOS or NO signaling need to allow for the complexity of local nitric oxide content and cellular context.
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Tarabees, Reda Zakaria Ibrahim. "Endotoxin induced muscle wasting in avian and murine skeletal muscle." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/13001/.
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This project was aimed to elucidate the sub-cellular and molecular regulation of Lipopolysaccharide (LPS) induced muscle protein turnover (protein synthesis (PS) and protein degradation) in two in vitro models, C2C12 murine myotubes and avian primary skeletal muscle cell line. In addition, the effect of natural challenge of chicken with Salmonella serotypes gallinarium or Enteritidis on mRNA expression levels in skeletal muscle was assessed. LPS (1 μgml-1) transiently decreased PS rate by 50% compared with control cells. This effect was mediated via decreased phosphorylation of translation initiation mediators (p70S6K, 4E-BP1 and eIF-4E). This effect was preceded by decreased Akt and mTOR phosphorylation. Although, LPS significantly increased p38, Erk1/2 and their down stream target Mnk1, however, this effect was not sufficient to abolish LPS-induced decreased PS. The role of Akt and MAPKs (p38 or Erk1/2) was verified using specific pathway inhibitors. Inhibition of Akt by LY0294002 (PI3-K/Akt inhibitor) dramatically decreased PS by 80% compared with control cells. Incubation of C2C12 myotubes with SB203580 (p38 inhibitor) or with PD098059 (MEK/Erk inhibitor) alone significantly decreased the PS rate at the 3 h time point by -63 ± 12.48% and -64 ± 5.05% respectively compared with control cells (P < 0.01). In contrast, LPS (1 μgml-1) significantly increased the chymotrypsin-like enzyme at all the time points. This effect was preceded by a significant increase in the IkB-α phosphorylation and nuclear translocation of NF-kB, and significant increase in TNF-α, atrogin-1, MuRF1 and TLR4 mRNA expression. Of note, increased atrogin-1 mRNA is the prominent feature of our septic model. The data presented in chapter 4 and 5 showed that, there is no absolute correlation between the expression levels of atrogens (atrogin-1 and MuRF1) and the overall proteolytic activity in LPS-stimulated C2C12 myotubes. The beneficial roles of the curcumin were evaluated LPS-stimulated C2C12 myotubes for 3 h. Incubation of C2C12 myotubes with LPS (1 μgml-1) and curcumin (25 μM) significantly decreased the LPS-induced chymotrypsin-like enzyme activity. This effect was mediated via decreased p38 and IkB-α phosphorylation. Although, curcumin blocked LPS-induced decreased Akt and p70S6K phosphorylation and significantly increased Erk1/2 phosphorylation, however, curcumin still had no effect on LPS-induced decreased protein synthesis. The effect of the LPS on the muscle protein turnover in the avian primary skeletal muscle was summarised in chapter (7). Incubation of avian primary skeletal cells with LPS (1 μgml-1) for 3 h, significantly decreased the proteasomal activity and increased PS rate. The difference in response to LPS between C2C12 myotubes and avian primary skeletal muscle cells could be attributed to the different incubation parameters mainly the presence of insulin in case of avian primary cells. Finally, the effect of natural challenge of chicken with S. Gallinarum or S. Enteritidis on skeletal muscle mRNA expression was summarised in chapter 9. Natural challenge of chicken with S. Gallinarum or S. Enteritidis had no effect on the expression of many atrophic genes in chicken skeletal muscle (gastrocnemius and pectoral muscle). The data collected from this project showed that, LPS is a strong catabolic stimulus significantly decreased PS along with increased protein breakdown rates in skeletal muscle. This effect was mediated via two main pathways PI3-K/Akt and MAPKs (p38 or Erk1/2) and the cross talk between them is exists. The better understanding of these signalling cascades and their cross talk will be the starting point for developing the appropriate and safe therapeutic intervention in order to decrease the sepsis-induced muscle proteolysis.