Dissertations / Theses: 'Skeletal muscle dysfunction and wasting'

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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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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.

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Puthucheary, Z. A. "Acute skeletal muscle wasting in the critically ill." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1425686/.

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Introduction: Critical illness survivors demonstrate skeletal muscle wasting with associated functional impairment. I prospectively characterised this process, and defined the pathogenic roles of altered protein synthesis and degradation. Methods: Critically ill patients (n=63, 59% male, age 54.7±18.0 years, APACHE II score 23.5±6.5) were recruited <24 hours following intensive care admission. Muscle loss trajectory was determined through serial ultrasound measurement of rectus femoris cross-sectional area (RFCSA) and, in a subset, quantification of myofibre area (FibreCSA) and protein/DNA ratio. Histopathological analysis was performed. Muscle protein synthesis and breakdown rates were determined and respective signalling pathways examined. Results: RFCSA decreased significantly, (-17.7±12.1%, [p<0.001]), underestimating muscle loss determined by FibreCSA (-10.3±10.9% vs.-17.5±30.2%, p=0.31), or protein/DNA ratio (-10.3±10.9% vs. -29.5±41.5%, p=0.03). Fall in RFCSA was greater in multi- than single-organ failure (-21.5±10.5% vs. - 7.2± 9.7%, p <0.0001), even by day 3 (-8.7±16.3% vs. -1.8± 9.6%, p<0.01). Myofibre necrosis occurred in >50% (20/37) of subjects. Protein synthesis was depressed to levels observed in fasted controls (0.035±0.018%/hr vs. 0.039±0.011%/hr, p=0.57), and increased by day 7 (0.076±0.066%/hr, p=0.03) to levels associated with fed controls (0.065+0.018%/hr, p=0.30,) independent of nutritional load. Protein breakdown remained elevated throughout (8.5±5.7 to 10.6±5.7mmol phe/min/IBW, p=0.4).Principal component analysis of intracellular signalling supported a programme of increased breakdown (r=-0.83, p=0.005) and depressed synthesis (r=-.69, p=0.041). Conclusions: Early rapid skeletal muscle wasting occurs in critical illness, is greatest in those with multi-organ failure, and results from suppression of protein synthesis and increases in catabolism. These effects are independent of feeding and are commonly associated with myonecrosis.

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Pickering, Warren Paul. "Regulation of metabolic acidosis-induced skeletal muscle wasting." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/30504.

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This work aims to investigate metabolic acidosis induced skeletal muscle protein wasting, and the inter-relationships between: metabolic acidosis, glucocorticoids (GC), and the ubiquitin proteasome system in this process.;Experiments were undertaken using three key themes and models: 1. The role of glucocorticoids and apoptosis in the process of protein degradation (PD) in L6G8C5 myoblasts in a cell culture system of metabolic acidosis utilizing dexamethasone and the glucocorticoid antagonist RU38486. Stimulation of PD in these cells by acid and GC does not appear to be an artefact of apoptosis or dedifferentiation, but differentiation state does determine whether PD responds spontaneously to acid or (as in vivo) only does so in the presence of GC. 2. The ability of RU38486 to pharmacologically antagonize the suggested permissive effect of glucocorticoid in an in vivo model of acidosis-induced muscle wasting. RU38486 did not prevent the acidosis-induced muscle wasting in this model despite demonstration of significant GC receptor blockade. 3. The role of the ATP-dependent ubiquitin proteasome system in the malnutrition of patients treated by peritoneal dialysis. When serum bicarbonate increased in these patients weight and body mass index increased significantly as did plasma BCAA. Muscle levels of ubiquitin mRNA decreased significantly; serum tumour necrosis factor-a also decreased. These results indicate that even a small correction of serum bicarbonate improves nutritional status, and provide evidence for down-regulation of BCAA degradation and muscle proteolysis via the ubiquitin proteasome system. Whether acidosis and inflammatory cytokines (such as TNF-alpha) interact to impair nutrition remains to be determined.

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Aydogdu, Tufan. "STAT3 Regulation of Skeletal Muscle Wasting in Cancer Cachexia." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/652.

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Cachexia is a highly complex syndrome identified by metabolic, hormonal and cytokine-related abnormalities, but can be shortly characterized as accelerated skeletal muscle and adipose tissue loss in the context of a chronic inflammatory response. Cachexia is a debilitating complication of several diseases such as AIDS, sepsis, diabetes, renal failure, burn injury and cancer. Cachexia is responsible for 25-30% of cancer patient deaths. One of the most obvious outcomes of cancer cachexia is the redistribution of the total protein content, namely the depletion of skeletal muscle protein levels and increase in the acute phase response protein levels as a response to tissue injury. Although the plasticity of muscle mass and utility of skeletal muscle as a protein source are known facts, there have not been many studies concerning the mechanism of conversion of skeletal muscle proteins to other protein forms, for which the organism has greater need. IL-6 and activation of the acute phase response have been linked to cancer cachexia. However, IL-6 is generally not thought to signal directly on skeletal muscle and to date no studies have manipulated the STAT3 pathway for regulating skeletal muscle mass. Our data demonstrate direct action of IL-6 on activation of the STAT3 and acute phase response pathway at the skeletal muscle. In addition, our observations that STAT3 is broadly activated in cachexia and that STAT3 activation is sufficient and necesssary to induce muscle wasting are also novel. Thus, these studies define a new pathway leading to muscle wasting, which can be a potential target for reversing muscle wasting in cancer cachexia. Successful inhibition of skeletal muscle wasting and other metabolic derangements of cachexia will increase quality of life and survival of a significant fraction of cancer patients.

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Antunes, Diana Sofia Ribeiro Duarte. "Lipidomic and proteomic in cancer-related skeletal muscle wasting." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/11613.

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Mestrado em Bioquímica Clínica
A caquexia associada ao cancro é uma condição fisiopatológica complexa caraterizada por acentuada perda de massa muscular.Recentemente, esta situação foi associada à disfunção mitocondrial. A relação e o papel do proteoma e lipidoma mitocondrial e a funcionalidade deste organelo permanece pouco compreendida, em particular no contexto do catabolismo muscular associado ao cancro. No sentido de melhor compreender os mecanismos moleculares subjacentes às alterações no músculo esquelético na caquexia associada ao cancro, utilizaram-se 23 ratos Wistar divididos aleatoriamente em dois grupos: com cancro da bexiga induzido pela exposição durante 20 semanas a N-butil-N-(4-hidroxibutil)-nitrosamina (grupo BBN, n=13) ou saudáveis (CONT, n=10). No final do protocolo verificou-se que os animais do grupo BBN apresentavam uma perda significativa de peso corporal e de massa muscular. Também foi observado uma diminuição da atividade da fosforilação oxidativa de mitocôndrias isoladas do músculo gastrocnemius. a qual foi acompanhada por alterações do perfil de fosfolípidos (PL) da mitocôndria. A alteração do lipidoma mitocondrial caraterizou-se pelo aumento do teor relativo de fosfatidilcolinas (PC) e fosfatidilserina (PS) e uma redução no teor relativo de cardiolipina (CL), ácido fosfatídico (PA), fosfatidilglicerol (PG) e fosfatidilinositol (PI). A análise realizada por GC-FID e HPLC-ESI-MS evidenciou ainda um aumento de ácidos gordos polinsaturados, com um aumento destacado de C22:6 em PC, PE e PS. A diminuição de CL foi acompanhada por diminuição na expressão de citocromo c e aumento da razão Bax/Bcl2, sugestivo de maior suscetibilidade à apoptose e stress oxidativo. Embora em níveis mais elevados, a UCP-3 não parece proteger as proteínas mitocondriais da lesão oxidativa atendendo ao aumento do teor de proteínas carboniladas. Em conclusão, a remodelação de PL da mitocôndria parece estar associada à disfunção da OXPHOS e, consequentemente, do catabolismo muscular associado ao cancro.
Cancer cachexia (CC) is a complex pathophysiological condition characterized by a marked muscle wasting. Recently, this situation has been associated to mitochondrial dysfunction. The interplay and role of mitochondrial proteome and lipidome and also the functionality of this organelle remains poorly understood in the context of cancer-related muscle wasting. To better understand the molecular mechanisms underlying skeletal muscle wasting, 23 Wistar rats were randomly divided in two groups: animals with bladder cancer induced by the exposition to N-butyl-N-(4-hydroxybutyl)-nitrosamine for 20 weeks (BBN, n=13) or healthy ones (CONT, n=10). At the end of the experimental protocol, BBN animals demonstrated a significant body weight and muscle mass loss and was also observed an decreased activity of oxidative phosphorylation in mitochondria isolated from gastrocnemius muscle, which was accompanied by alterations of this organelle’s phospholipids (PL) profile. The mitochondrial lipidome alterations were characterized by an increase of the relative content of phosphatidylcholines (PC) and phosphatidylserine (PS) and a decrease of cardiolipin (CL), phosphatidic acid (PA), phosphatidylglycerol (PG) and phosphatidylinositol (PI). GC-FID and HPLC-ESI-MS analysis also showed an increase of polyunsaturated fatty acids, particularly of C22:6 in PC, PE and PS. The observed decrease in CL class was accompanied by a decrease in the expression of cytochrome c, and an increase of the ratio Bax/Bcl-2, suggestive of a greater susceptibility to apoptosis and oxidative stress. Although in higher levels, UCP-3 does not seem to protect mitochondrial proteins from oxidative damage considering the increased content of carbonylated protein. In conclusion, the PL remodeling seems to be associated to OXPHOS dysfunction and consequently to muscle catabolism associated with cancer.

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Aare, Sudhakar Reddy. "Intensive Care Unit Muscle Wasting : Skeletal Muscle Phenotype and Underlying Molecular Mechanisms." Doctoral thesis, Uppsala universitet, Klinisk neurofysiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-180374.

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Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors. The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

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Moore, Tamara W. I. "The role of USP19 in denervation induced skeletal muscle wasting." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=94923.

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Skeletal muscle wasting can be a fatal complication of many diseases, such as cancer, AIDS and neuromuscular disorders. During wasting, the ubiquitin-proteasome system (UPS) is the primary pathway for the catabolism of myofibrillar proteins. Many studies have explored the importance of enzymes mediating the conjugation of ubiquitin to muscle proteins. However, the role of deubiquitinating enzymes in skeletal muscle wasting is poorly understood. Our laboratory previously identified USP19 as a deubiquitinating enzyme which is upregulated in response to atrophic stimuli in vivo and is capable of indirectly regulating the expression of myofibrillar proteins in muscle cells in vitro. However, the role of USP19 during skeletal muscle wasting in vivo remains unexplored. To address this question, I have characterized the phenotype of USP19 KO mice and determined the effects of denervation induced wasting of hindlimb muscles of USP19 KO mice by measuring various anatomical and structural parameters. Denervation stimulus was chosen to minimize number of animals used since control and treated limbs are within the same animal. USP19 KO mice had slightly heavier gastrocnemius muscle (GAS) mass than WT mice, with a trend towards a larger fiber size and higher protein content. After denervation, the skeletal muscle mass of KO mice is 30% heavier than that of denervated WT mice in both the tibialis anterior (TA) and GAS muscle. This significant sparing is correlated with KO having 30% more protein than WT in GAS muscles, after denervation. The level of the myofibrillar protein tropomyosin was significantly higher in denervated KO GAS than in denervated WT GAS, consistent with previous USP19 siRNA studies in rat skeletal muscle cells. Although, structural analysis of denervated GAS fiber reveals a small but significant sparing in the fiber size of KO mice as compared to WT mice, this difference only accounts for 5% of the mass sparing observed in KOs. Loss of neural stimulation
L'atrophie musculaire est une grave complication qui peut être fatale dans plusieurs maladies comme le cancer, le SIDA ou les maladies neuromusculaires. Le système ubiquitine-protéasome (UPS) est le mécanisme le plus impliqué dans la dégradation des protéines myofibrillaires durant l'atrophie. Plusieurs études ont démontré l'importance de certaines enzymes catalysant la conjugaison de l'ubiquitine aux protéines musculaires. Parcontre, le rôle des enzymes de déubiquitination durant l'atrophie musculaire est encore très peu connu. Notre laboratoire a précédemment identifié USP19, une enzyme de déubiquitination, qui est régulée à la hausse en réponse à plusieurs stimuli d'atrophie musculaire in vivo et qui est aussi capable de réguler indirectement des protéines myofibrillaires dans des cellules musculaires in vitro. Toutefois, le rôle de USP19 dans l'atrophie musculaire in vivo est encore inconnu. Afin d'aborder cette question, j'ai caractérisé le phénotype de souris dont le gène USP19 a été inactivé (KO) et j'ai déterminé les effets d'une dénervation des muscles de la patte postérieur sur ces souris KO en mesurant divers paramètres anatomiques et structuraux. Les souris USP19 KO possèdent une masse du muscle gastrocnemius (GAS) légèrement plus grande que les souris contrôles (WT) avec une tendance vers des fibers plus grosses et un contenu protéique plus élevé. Après dénervation, les muscles squelletiques des souris KO étaient 30% plus lourds que ceux des souris WT et ce dans le GAS ainsi que dans le tibialis postérieur (TA). Cette économie significative corrèle bien avec une augmentation de 30% du contenu protéique dans les muscles KO (GAS) comparé aux muscles WT, après dénervation. Aussi, les niveaux de la protéine myofibrillaire tropomyosine étaient significativement plus élevés dans le GAS KO que dans que dans le GAS WT, après dénervation, ce qui est consistant avec des études postérieures de siRNA

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Rosa, Hannah Sophia. "Pathogenesis of mitochondrial dysfunction in skeletal muscle." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3969.

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Mitochondrial diseases are amongst the most prevalent genetic disorders, however little is known about genetic and cellular mechanisms behind disease pathogenesis and progression. Elucidating such mechanisms can help identify targets for novel therapeutic measures and improve patient care by informing the implementation of clinical regimens and providing clearer information on prognoses. This project aims to improve the understanding of the molecular mechanisms behind the pathogenesis of mitochondrial dysfunction in muscle and the genetic and biochemical changes occurring over time in patients with mitochondrial disease. Firstly, a longitudinal study combines immunofluorescent and molecular genetic techniques to assess biochemical and genetic changes over time in serial skeletal muscle biopsies from patients with m.3243A > G or single, large-scale mtDNA deletions, the two largest groups in the MRC Centre Mitochondrial Disease Patient Cohort. Further investigation into the relationship between the genetic and biochemical defects in patients with single, large-scale mtDNA deletions is carried out by applying a single-fibre approach. Here, muscle fibres are classified by their biochemical defect and laser microdissected for genetic analysis to determine deletion level and mtDNA copy number. These studies find that: (i) changes to mutation level, mtDNA copy number and biochemical defect occur over time in skeletal muscle of mitochondrial disease patients; (ii) these changes are inconsistent in magnitude and direction across groups of patients and (iii) the biochemical threshold for deficiency is affected by the size and location of single, large-scale mtDNA deletions. In addition, a real time PCR assay for the quantification of mitochondrial DNA copy number from homogenate tissue has been optimised to improve accuracy through the use of additional gene markers.

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Pattison, J. Scott. "Understanding muscle wasting through studies of gene expression and function." Free to MU Campus, others may purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p3164536.

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Vineham, Jennifer. "Smac Mimetic Compound Treatment Induces Tumour Regression and Skeletal Muscle Wasting." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31528.

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Of all of the cancer patients throughout the world, approximately 50% of them are affected to some degree by cachexia. This syndrome involves significant skeletal muscle wasting, loss of adipose tissue and overall decrease in body weight in patients, particularly those with lung, pancreatic and gastric cancers. Cancer-induced cachexia is characterized by the presence of increased cytokines, notably TNF-α, IL-1β and IL-6. Most patients suffering of cancer-induced cachexia experience increased toxicity in response to chemotherapy, leading to fewer rounds of treatment and thus impeding the patients’ chances for recovery. More research into effective treatments for cancer-induced cachexia would therefore be indispensable. The inhibitor of apoptosis proteins (IAPs) have emerged as important cancer targets, primarily because of their roles as caspase inhibitors and regulators of NF-κB signalling. Small molecule IAP antagonists known as Smac mimetic compounds (SMCs) are currently in stage I/II clinical trials. They function by targeting cIAP1 and cIAP2 (and to a lesser extent, XIAP) resulting in a cytokine mediated death response in cancer cells. SMCs induce the production of TNF-α, a cytokine with which SMCs can potently synergize. However, limited efficacy occurs in some cancer cell lines (presumably because TNF-α cannot be induced in an autocrine fashion) and an exogenous source of the cytokine, such as that induced by using an oncolytic virus, is required. Notably, TNF-α (initially known as “cachectin”) is known to play a significant role in the induction of skeletal muscle atrophy. We therefore wanted to examine the effects of TNF-α induction by SMC and oncolytic virus co-treatment on both tumour regression and skeletal muscle in tumour bearing mice. We investigated the effects of SMC treatment on Lewis Lung Carcinoma (LLC) and B16F10 melanoma cell lines, both of which have been shown to be established cachectic cancer cell lines. Our in-vitro analysis of LLC and B16F10 cells revealed that LLC cells are sensitive to SMC and TNF-α co-treatment whereas B16F10 cancer cells remain resistant. SMC treatment, in combination with an oncolytic virus, VSVΔ51, increased tumour regression and survival time in LLC tumour bearing mice. Based on findings from previous studies, we investigated the role of cellular FLICE-like inhibitory protein (c-FLIP) in the resistance of the B16F10 melanoma cell line to SMC treatment. We were able to determine that the down-regulation of c-FLIP sensitizes the B16F10 cells to SMC and TNF-α induced cell death. In extending these findings, we found that SMC treatment alone can cause skeletal muscle wasting in the tibialis anterior muscle of LLC tumour bearing mice. However, the atrophic response was observed to be minimal as documented by a slight but significant decrease (approximately 10%) in muscle fibre cross-sectional area. Moreover, no biochemical evidence of muscle atrophy, as visualized by changes in the expression of myosin heavy chain (MHC) and Muscle RING Finger protein 1 (MuRF1), was found. Regardless, we speculate that the impact of SMC treatment on muscle wasting would be transient and reversible, and propose that the benefits of such a combination immunotherapy would greatly outweigh the risks.

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Hopkinson, Nicholas Shaun. "Skeletal muscle dysfunction in chronic obstructive pulmonary disease." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417140.

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Swallow, Elisabeth. "Skeletal muscle dysfunction in chronic obstructive pulmonary disease." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508993.

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Acharyya, Swarnali. "Elucidating molecular mechanisms of muscle wasting in chronic diseases." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1180096565.

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Skipworth, Richard John Edward. "Mediators, mechanisms and biomarkers of skeletal muscle wasting and function in cancer cachexia." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/25193.

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Cachexia is a syndrome of progressive nutritional depletion that occurs in up to one-half of all patients with cancer. In particular, cachexia involves a severe and specific loss of skeletal muscle, which is associated with worsened patient morbidity, reduced quality of life (QoL), and increased mortality. The aims of this thesis were to investigate specific mediators, mechanisms and biomarkers of muscle wasting and function in cancer cachexia. Models included human cancer cell lines and tissue samples, and patients with different types of upper gastrointestinal (GI) cancer. Upper GI cancer was chosen as the model for investigation as such patients are known to have a high prevalence of cachexia. Tumour-derived cachectic mediators were investigated initially (Chapters 3 to 5). There has been much speculation about whether the murine tumour-derived cachectic mediator known as proteolysis-inducing factor (PIF) has a human homologue, and how this may be derived from a larger gene known to encode for dermcidin, an anti-microbial peptide found in sweat. Messenger ribonucleic acid (mRNA) expression levels of dermcidin were analysed in human tumour tissue and human cancer cell lines. Expression of dermcidin was highly variable in human tumours, but appeared to be largely absent or expressed at only very low levels in oesophago-gastric cancer and prostate cancer (Chapter 3). Additionally, although human cell lines did express dermcidin mRNA, sequence analysis of complementary DNA (cDNA) derived from this mRNA demonstrated that transcripts lacked a site for the glycosylation critical to the proteolysis-inducing activity of murine PIF, thus raising doubt about the existence of human PIF (Chapter 4). Attention was then focused on plasma concentrations of macrophage inhibitory cytokine-1 (MIC-1), another potential tumour-derived mediator of cachexia in humans (Chapter 5). In a cohort of patients with oesophago-gastric cancer (n=293), although MIC-1 concentrations correlated with systemic inflammation (a key component of the cachexia syndrome), there was no independent link between plasma MIC-1 and nutritional status or survival. Thus, further investigations are required before MIC-1 can be determined as a key mediator of cancer cachexia in humans. Next, the role of circulating neuroendocrine mediators, specifically sex steroids and gonadotropins, were investigated in a cohort of patients with advanced pancreatic cancer (n=175) (Chapter 6). Testosterone is known to be a significant determinant of muscle mass. However, 73% of male cancer patients were hypogonadal (as defined by calculated serum free testosterone). Hypogonadal males demonstrated shortened survival compared with eugonadal males. Furthermore, male opioid use (an iatrogenic cause of male hypogonadism) was associated with shortened survival. In contrast, 18% of postmenopausal females exhibited premenopausal or 'hyperoestrogenic' serum oestradiol levels. Hyperoestrogenic females demonstrated shortened survival compared with eugonadal females. Thus, clinical trials of androgen replacement therapy (particularly in the presence of opioid analgesia) may be a potential route forwards in males with non-hormone sensitive types of cancer. Regulatory mechanisms of protein degradation within skeletal muscle were then examined (Chapters 7 and 8). It has been suggested that there may be parallels in the mechanisms of muscle wasting observed in genetic disorders, such as the muscular dystrophies, and the mechanisms observed in acquired conditions such as cancer cachexia. In rectus abdominis muscle samples from patients with oesophago-gastric cancer (n=27), deregulation of the sarcolemma-bound, muscular dystrophy-associated dystrophin glycoprotein complex (DGC) (involving reduced expression of dystrophin and hyperglycosylation of key DGC proteins) was found in 17/27 (63%) samples (Chapter 7). Moreover, the presence of DGC deregulation was associated with worsened patient function and shortened patient survival. These results suggest a possible common pathway between genetic and acquired forms of muscle wasting. The mass of a muscle is determined by the balance between protein synthesis and degradation. Pathways that can both increase protein degradation and suppress synthesis could have a profound influence on the rate of muscle wasting. Levels of the activated (phosphorylated) forms of the dsRNA-dependent protein kinase (PKR) and eukaryotic translation initiation factor 2a (eEF2a), intracellular mediators in pathways leading to increased muscle protein degradation and reduced protein synthesis, were determined in rectus abdominis samples from oesophago-gastric cancer patients (n=15) (Chapter 8). Levels of both phospho PKR and phospho eIF2a were significantly enhanced in muscle from cachectic patients, and there was a linear relationship between myosin expression and the extent of eIF2a phosphorylation. These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer cachexia. Next, the presence of urinary biomarkers of skeletal muscle wasting were analysed using mass spectrometry in urine samples from cachectic oesophago-gastric cancer patients (n=8), weight-stable cancer patients (n=8) and healthy controls (n=8) (Chapter 9). The identification of early biomarkers of cachexia, the clinical detection of which would allow the institution of prophylactic therapeutic measures, is one of the key areas of need in cancer cachexia research. The number of protein species identified in urine samples from cachectic cancer patients (n=199) was significantly greater than that identified in samples from weight-stable cancer patients (n=79) and controls (n=49). Proteins identified specifically in cachectic samples, and thus potential biomarkers of muscle wasting that could be utilised in future clinical trials, included muscle (myosin species), cytoskeletal, and microtubule-associated proteins. Lastly, the use of objective assessment of physical activity as a potential biomarker of skeletal muscle function, and thus a novel outcome measure in the clinical management of advanced cancer patients, was explored (Chapters 10 and 11). Criterion-based validation of estimates of energy expenditure using an accelerometer-based activity-monitoring system (activPAL™) was performed using a combination of doubly labelled water and indirect calorimetry in cancer patients (n=6) and healthy controls (n=9) (Chapter 10). Although absolute errors for activPAL™-derived estimates of mean energy expenditure of activity (1.4%) and mean total energy expenditure (0.4%) were low, there was considerable variability in individual patient results, suggesting that further prospective validation studies of energy expenditure are required. (Step count and other PA measures have been validated previously). The activPAL™ meter was also used to take sequential measurements of objective PA in a cohort of patients with upper GI cancer undergoing palliative chemotherapy (n=16) (Chapter 11). Recruited patients demonstrated a complex "journey" of PA during treatment, with individuals describing worsened, improved or unchanged PA. However, the overall trend was one of deterioration in PA during chemotherapy. Importantly, objective measures of PA correlated with subjective scores of QoL, fatigue and performance status, supporting the use of objective PA as a patient-centred outcome. In summary, certain circulating mediators (sex steroids) and intracellular mechanisms (DGC deregulation and PKR phosphorylation) have been shown to be important in the aetiology of cachexia/skeletal muscle wasting in cancer, and the determination of patient outcome. Urinary biomarkers of muscle protein degradation (myosin species) and biomarkers of muscle function (physical activity) may be useful as inclusion criteria and/or outcome measures in clinical trials of anti-cachexia therapies.

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16

Piper, Tony Andrew. "A study of the transfer of recombinant dystrophin genes into skeletal muscle cells." Thesis, Royal Holloway, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286683.

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17

Kanaan, Georges. "Mitochondrial Dysfunction: From Mouse Myotubes to Human Cardiomyocytes." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37582.

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Mitochondrial dysfunction is a common feature in a wide range of disorders and diseases from obesity, diabetes, cancer to cardiovascular diseases. The overall goal of my doctoral research has been to investigate mitochondrial metabolic dysfunction in skeletal and cardiac muscles in the context of chronic disease development. Perinatal nutrition is well known to affect risk for insulin resistance, obesity, and cardiovascular disease during adulthood. The underlying mechanisms however, are poorly understood. Previous research from our lab showed that the in utero maternal undernutrition mouse model is one in which skeletal and cardiac muscle physiology and metabolism is impaired. Here we used this model to study the impact of in utero undernutrition on offspring skeletal primary muscle cells and to determine if there is a cell autonomous phenotype. Metabolic analyses using extracellular flux technologies revealed a shift from oxidative to glycolytic metabolism in primary myotubes. Gene expression profiling identified significant changes in mRNA expression, including an upregulation of cell stress and OXPHOS genes and a downregulation of cell division genes. However, there were no changes in levels of marker proteins for mitochondrial oxidative phosphorylation (OXPHOS). Findings are consistent with the conclusion that susceptibility to metabolic disease in adulthood can be caused at least in part by muscle defects that are programmed in utero and mediated by impaired mitochondrial function. In my second project, the effects of the absence of glutaredoxin-2 (Grx2) on redox homeostasis and on mitochondrial dynamics and energetics in cardiac muscle from mice were investigated. Previous work in our lab established that Grx2-deficient mice exhibit fibrotic cardiac hypertrophy, and hypertension, and that complex I of OXPHOS is defective in isolated mitochondria. Here we studied the role of Grx2 in the control of mitochondrial structure and function in intact cells and tissue, as well as the role of GRX2 in human heart disease. We demonstrated that the absence of Grx2 impacts mitochondrial fusion, ultrastructure and energetics in mouse primary cardiomyocytes and cardiac tissue and that provision of the glutathione precursor, N-acetylcysteine (NAC) did not restore glutathione redox or prevent impairments. Furthermore we used data from the human Genotype-Tissue Expression consortium to show that low GRX2 expression is associated with increased fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, our results indicate that GRX2 plays a major role in cardiac mitochondrial structure and function, and protects against left ventricle pathologies in humans. In my third project, we collaborated with cardiac surgeon, Dr. Calum Redpath, of the Ottawa Heart Institute to study atrial mitochondrial metabolism in atrial fibrillation patients with and without type 2 diabetes (T2DM). T2DM is a major risk factor for atrial fibrillation, but the causes are poorly understood. Atrial appendages from coronary artery bypass graft surgery were collected and analyzed. We showed an impaired complex I respiration in diabetic patients with atrial fibrillation compared to diabetic patients without atrial fibrillation. In addition, and for the first time in atrial fibrillation patients, mitochondrial supercomplexes were studied; results showed no differences in the assembly of the “traditional” complexes but a decrease in the formation of “high oligomeric” complexes. A strong trend for increased protein oxidation was also observed. There were no changes in markers for OXPHOS protein levels. Overall findings reveal novel aspects of mitochondrial dysfunction in atrial fibrillation and diabetes in humans. Overall, our results reveal that in utero undernutrition affects the programming of skeletal muscle primary cells, thereby increasing susceptibility to metabolic diseases. In addition, we show that GRX2 impacts cardiac mitochondrial dynamics and energetics in both mice and humans. Finally, we show impaired mitochondrial function and supercomplex assembly in humans with atrial fibrillation and T2DM. Ultimately, understanding the mechanisms causing mitochondrial dysfunction in muscle tissues during chronic disease development will increase our capacity to identify effective prevention and treatment strategies.

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Shrikrishnapalasuriyar, Dinesh. "ACE-inhibition and skeletal muscle dysfunction in chronic obstructive pulmonary disease." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/39299.

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This thesis addresses the impact of quadriceps wasting and physical inactivity across disease severity (GOLD stages I-IV) in Chronic Obstructive Pulmonary Disease (COPD) and assesses the influence of angiotensin-converting enzyme (ACE)-inhibition on quadriceps dysfunction in these patients. In a cross-sectional study of 161 COPD patients, ultrasound measurement of rectus femoris cross-sectional area was reduced in mild as well as advanced disease when compared to controls. Daily physical activity, measured using an armband accelerometer, was reduced in COPD subjects across all GOLD stages compared to controls. Physical activity was independently associated with quadriceps wasting in GOLD stage I, but not stage II-IV disease where residual volume to total lung capacity ratio was the only independent predictor of activity level. This data suggests that quadriceps wasting is not an end-stage phenomenon in COPD and highlights the need for early identification of these patients to guide lifestyle and therapeutic interventions. The effect of the ACE-inhibitor, fosinopril on quadriceps dysfunction in COPD was then investigated in a double-blind randomised controlled trial of 80 COPD patients with quadriceps weakness. Despite a significant reduction in systolic blood pressure and serum ACE activity in the treatment group compared to placebo, no significant differences were observed at 3 months in the primary outcome of non-volitional quadriceps endurance. Quadriceps strength improved in both groups, but there was a greater increase in the placebo arm. No significant changes were observed in mid-thigh cross-sectional area or incremental shuttle walk distance. The trial also assessed the effect of ACE-inhibition on vastus lateralis atrogene expression in COPD, with no significant differences observed between groups. In conclusion, although evidence from observational cohorts suggest a role for the renin-angiotensin system in the control of muscle phenotype, data from this thesis found that ACE-inhibition did not improve quadriceps function in a COPD population with quadriceps weakness.

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Cornwell, Evangeline Wang. "Colon-26 cancer-induced skeletal muscle wasting is IKKbeta/IkappaBalpha-dependent and NF-kappaB-Independent." Thesis, Boston University, 2014. https://hdl.handle.net/2144/10972.

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Thesis (Ph.D.)--Boston University
Existing data suggest that NF-kappaB signaling is a key regulator of cancer-induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-kappaB transcription factors that regulate wasting is far from complete. In muscles of C26 tumor-bearing mice, overexpression of dominant-negative (d.n.) IKKbeta and the IkappaBalpha-super repressor blocked wasting by 69% and 41%, respectively. In contrast, overexpression of d.n. IKKalpha or d.n. NIK did not block C26-induced muscle wasting. Surprisingly, overexpression of d.n. RelA (p65) or d.n. c-Rel did not significantly affect muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-kappaB transcription factors, we compared genome-wide p65 binding to DNA in control and cachectic muscle using chromatin immunoprecipitation-sequencing (ChiP-seq). Bioinformatic analysis of ChiP-sequencing data from control and C26 muscles did not show p65 binding peaks in the upregulated genes as reflected by the expression arrays. The p65 ChiP-seq data are consistent with our finding of no significant change in protein binding to an NF-kappaB oligonucleotide in an electrophoretic mobility shift assay (EMSA), no activation of an NF-kappaB-dependent reporter, and no effect of d.n. p65 overexpression in muscles of tumor-bearing mice. Taken together, these data support the idea that although inhibition of IkappaBalpha, and particularly IKKbeta, blocks cancer-induced muscle wasting, the alternative NF-kappaB signaling pathway is not required. In addition, the downstream NF-kappaB transcription factors are not involved in gene regulation during atrophy. These data are consistent with the growing body of literature showing that there are NF-kappaB-independent activities of IKKbeta and IkappaBalpha that regulate physiological processes.

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Haynie, Kimberly Rebekah. "The Role of Neuropeptide Y Y1R in Skeletal Muscle Lipid Metabolism." Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/32270.

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The Hulver laboratory has recently found that the neuropeptide Y Y1 receptor (NPY Y1R) mRNA expression is elevated in skeletal muscle of obese humans (Hulver, unpublished). The goal of this research is to study the role of the NPY Y1R in skeletal muscle lipid metabolism.

Rat L6, mouse C2C12, and human primary myotubes were incubated in 14C palmitate labeled fatty acid oxidation medium containing 80ng/mL, 250ng/mL, and 500ng/mL of NPY and for a three hour period. Experiments were repeated with the addition of 17mg/mL diprotin A to each NPY treatment. Fatty acid oxidation (FAO) and the percentage of lipids stored within the myotubes as diacylglyceride (DAG) and triaclyglyceride (TAG) were measured. Analyses were repeated in rat L6 and mouse C2C12 following a three hour incubation in 14C palmitate labeled fatty acid oxidation medium containing 1Âµg/mL, 10Âµg/mL, and 50Âµg/mL of the NPY Y1R ligand, [Leu31, Pro34] neuropeptide Y (Bachem, Torrance, CA).

Incubation of human primary myotubes in NPY treatments with the addition of diprotin A significantly increased TAG accumulation (p< 0.05). Mouse C2C12 mytoube incubation in 500ng/mL NPY with diprotin A increased FAO (p 0.05). All other NPY and NPY Y1R ligand treatments in had no significant effect on FAO or the accumulation of TAG and DAG.
Master of Science

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21

Patel, Mehul Sureshchandra. "The manifestations of ageing in the pathophysiology of skeletal muscle dysfunction in COPD." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/30839.

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The aim of this thesis was to address the impact of the skeletal muscle adaptations that occur in Chronic Obstructive Pulmonary Disease (COPD) and subsequently to identify tools that may be relevant in the management of patients with structural and functional muscle abnormalities. To establish whether the type I to II fibre shift that occurs in COPD is associated with mortality, a retrospective multicentre analysis of 392 stable COPD outpatients was performed. Across the whole cohort, fibre shift was an independent predictor of mortality in a model also including age and FEV1%predicted. In patients with GOLD stage III or IV disease, quadriceps strength, but not fibre shift had an independent association with an increased risk of mortality. Therapies targeting quadriceps fibre shift and weakness may be of therapeutic value; practical tools that identify relevant patients may have clinical utility. Since the pathophysiological adaptations that occur may be considered to be a manifestation of accelerated biological ageing, potentially relevant physical and biological markers of ageing were identified following a review of the literature. The Short Physical Performance Battery (SPPB) is used in gerontology to assess lower limb function, but its determinants have not been previously evaluated in COPD. SPPB score was measured in 109 stable COPD outpatients; 31 also had a quadriceps biopsy. Quadriceps strength and exercise capacity were the only independent predictors of SPPB score. Stratification by SPPB score identified patients with locomotor muscle atrophy and impairment in strength, exercise capacity and daily physical activity. Patients with a reduced SPPB score had a higher proportion of type II fibres. Subsequently, the SPPB potentially has practical utility in the assessment of COPD patients. Systemic Klotho and GDF-15 levels are associated with mortality in non-selected populations; these proteins were evaluated initially in the serum and then the skeletal muscle of healthy controls, smokers and COPD patients. Circulating Klotho levels were reduced in COPD and smokers, related to quadriceps strength and increased after successful smoking cessation. Serum GDF-15 levels were elevated in COPD, and related to a marker of systemic oxidative damage and locomotor muscle atrophy. Klotho and GDF-15 were expressed in skeletal muscle. Quadriceps GDF-15 expression was elevated in COPD patients as compared to controls and diaphragm expression. Klotho levels were reduced in the locomotor muscle of human smokers and smoke-exposed mice. Humans had relatively higher Klotho levels in respiratory muscle. Quadriceps Klotho levels positively correlated with local protein carbonylation and were also unexpectedly elevated in patients with established skeletal muscle dysfunction; immunohistochemistry confirmed that Klotho was associated with regenerating muscle fibres. Modulation of Klotho and GDF-15 signalling, and potentially other age-related molecules, may provide therapeutic options to COPD patients.

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22

Fermoselle, Pérez Clara 1985. "Molecular mechanisms involved in the process of muscle wasting : human and animal studies." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/116734.

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Muscle dysfunction and muscle wasting are major systemic manifestations of chronic conditions such as Chronic Obstructive Pulmonary Disease (COPD) and cancer. Several biological mechanisms contribute to such a dysfunction. Our objectives were to identify cellular and molecular mechanisms involved in the respiratory and peripheral muscle dysfunction of cachexia models associated with chronic respiratory conditions. The diaphragm and gastrocnemius of mice [emphysema and lung cancer (LC) models] and the vastus lateralis of severe COPD patients were studied with their respective healthy controls. Muscle structure was analyzed in the animal LC model and in the COPD human model. Several biological markers were studied: proteolysis markers, signaling pathways related to proteolysis, redox balance and inflammation. Mitochondrial respiratory chain was also explored in the LC mice model. In all three models the cachectic subjects were identified using total body weight. In patients, fat-free mass index was also identified. In the mouse models, muscle weights were also determined. They were decreased in all cachectic animals compared to the controls. Muscle structure was affected in the cachectic subjects: LC cachectic mice showed a decrease in both type I and II fibers size, while muscle-wasted COPD patients showed a decrease in type II fiber sizes and in proportions of type I fibers. Proportions of myofiber abnormalities were greater in both LC cachectic animals and muscle-wasted COPD patients. Only LC cachectic mice showed higher levels of IFNγ in the diaphragm. Oxidative stress, proteolysis markers and NFκB pathway were enhanced in the muscles of the cachectic subjects in the three models. Mitogen-activated protein kinases (MAPK) and forkhead box (FoxO) signaling pathways were enhanced in the muscles of the cachectic mice. Myogenin levels were reduced in the muscles of all three models. Myostatin levels were greater in the muscles of the cachectic mice. Mitochondrial function was depressed in both respiratory and limb muscles of the LC cachectic mice. We conclude that enhanced protein catabolism and mitochondrial dysfunction occurs in the muscles of these cachexia models (both patients and animals). Major signaling pathways such as NF-kB and FoxO are involved in this process. These findings offer future therapeutic strategies in cachexia associated with chronic respiratory conditions.

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23

Wredenberg, Anna. "Mitochondrial dysfunction in ageing and degenerative disease /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-311-5/.

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24

Watson, Maria. "The role of palmitate in skeletal muscle cell insulin resistance and pancreatic beta cell dysfunction." Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505620.

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25

Salah, Heba. "Muscle Wasting in a Rat ICU Model : Underlying Mechanisms and Specific Intervention Strategies." Doctoral thesis, Uppsala universitet, Klinisk neurofysiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328596.

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Critical care has undergone several developments in the recent years leading to improved survival. However, acquired muscle weakness in the intensive care unit (ICU) is an important complication that affects severely ill patients and can prolong their ICU stay. Critical illness myopathy (CIM) is the progressive decline in the function and mass of the limb muscles in response to exposure to the ICU condition, while ventilator-induced diaphragm dysfunction (VIDD) is the time dependent decrease in the diaphragm function after the initiation of mechanical ventilation. Since the complete underlying mechanisms for CIM and VIDD are not completely understood, there is a compelling need for research on the mechanisms of CIM and VIDD to develop intervention strategies targeting these mechanisms. The aim of this thesis was to investigate the effects of several intervention strategies and rehabilitation programs on muscle wasting associated with ICU condition. Moreover, muscle specific differences in response to exposure to the ICU condition and different interventions was investigated. Hence, a rodent ICU model was used to address the mechanistic and therapeutic aspects of CIM and VIDD. The effects of heat shock protein 72 co-inducer (HSP72), BGP-15, on diaphragm and soleus for rats exposed to different durations of ICU condition was investigated. We showed that 5 and 10 days treatment with BGP-15 improved diaphragm fiber and myosin function, protected myosin from posttranslational modification, induced HSP72 and improved mitochondrial function. Moreover, BGP-15 treatment for 5 days improved soleus muscle fibers function, improved mitochondrial structure and reduced the levels of some ubiquitin ligases. In addition to BGP-15 treatment, passive mechanical loading of the limb muscles was investigated during exposure to the ICU condition. We showed that mitochondrial dynamics and mitophagy gene expression was affected by Mechanical silencing while mechanical loading counteracted these effects. Our investigation for other pathways that can be involved in muscle wasting associated with ICU condition showed that the Janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is differentially activated in plantaris, intercostals and diaphragm. However, further studies are required with JAK2/STAT3 inhibitors to fully examine the role of this pathway in the pathogenesis of CIM and VIDD prior to translation to clinical research.

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26

Barker, Bethan Louise. "Exploring the interplay between airway bacteria, airway inflammation, lung structure and skeletal muscle dysfunction in COPD." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/39977.

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Airway bacteria, airway inflammation, lung structure and skeletal muscle dysfunction are all recognised as important components of chronic obstructive pulmonary disease (COPD), yet the interplay between these components is not well understood. Within this thesis I present an observational study exploring relationships between airway inflammation and molecular measures of potentially pathogenic bacteria. I have shown that airway bacterial detection is associated with increased airway inflammation in stable COPD, and that this association appears to be driven by Haemophilus influenzae. I then present a cross-sectional and longitudinal study using dual energy x-ray absorptiometry measurements of body composition and have shown that airway bacterial load and inflammation are independent of body composition changes, and that loss of skeletal muscle is not associated with accelerated airway inflammation or lung function decline. Within a multi-centre exacerbation cohort study I have shown that sputum bacterial load is only weakly associated with quadriceps muscle strength in stable COPD. In addition I have shown only a small, short-lived reduction in quadriceps strength at exacerbation, suggesting that community managed exacerbations may have limited impact on long term decline in muscle and physical function in COPD patients. Finally, I present the results of a single centre study that has shown that air trapping measured using quantitative computed tomography (QCT) makes the strongest unique contribution to airflow obstruction in COPD. Moreover, H. influenzae bacterial load is related to QCT measured small airways disease, and this association is independent of the amount of neutrophilic airways inflammation. In summary, within this thesis I provide data demonstrating significant relationships between H. influenzae, airway inflammation and lung structural changes in COPD. By contrast, my findings suggest that inflammation, and in particular overspill of pulmonary inflammation is not a key pathophysiological mechanism leading to skeletal muscle depletion or dysfunction in COPD.

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27

Lowman, John D. Jr. "Effects of emphysema and chronic hypoxemia on skeletal muscle oxygen supply and demand." VCU Scholars Compass, 2004. http://scholarscompass.vcu.edu/etd/907.

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Skeletal muscle dysfunction in chronic obstructive pulmonary disease (COPD) is a condition in which peripheral skeletal muscle undergoes myopathic changes which impair muscle function, limit physical performance, and can lead to significant disability. While the etiology of the dysfunction is unknown, this study was conducted to test the hypothesis that chronic hypoxemia leads to alterations in oxygen transport and muscle function. A primary objective was to validate elastase-induced emphysema in rats as an animal model of skeletal muscle dysfunction in COPD.Arterial blood gases were used to determine the severity of hypoxemia and sodium dodecyl sulfate- polyacrylamide gel electrophoresis was used to determine the proportions of myosin heavy chain isoforms I, IIa, IIx, and IIb. Measures of microvascular oxygenation and blood flow in the spinotrapezius muscle allowed for determination of both convective and diffusive oxygen supply to the muscle, as well as calculation of muscle oxygen consumption at rest and during electrically stimulated three-minute muscle contractions. Muscle performance measures included peak force, force-time integral, and fatigue index. Due to a presumed rat respiratory virus, which likely resulted in the control group being nearly as hypoxemic as the elastase-induced emphysema group, this study was not able to definitively test the hypothesis that chronic hypoxemia leads to both a diminished supply and demand of oxygen in skeletal muscle. Although many of the results of the present study were not statistically significant, they exhibited consistent trends over time and are likely of physiological significance. All measures of muscle performance were lower in the emphysema group. In addition, spinotrapezius muscle oxygen consumption and blood flow were lower in the emphysema group. The addition of supplemental oxygen during isolated, small-muscle mass exercise did increase the force-time integral by ~18% in both groups, suggesting that muscle work in these hypoxemic animals may be limited by oxygen supply. Thus, the data on muscle fiber type, oxygen consumption and muscle performance suggest that elastase-induced emphysema in rats leads to a similar skeletal muscle dysfunction that is observed in humans with COPD, and indicates that it is a valid animal model of skeletal muscle dysfunction in COPD.

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Struthers, Kyle Remington. "ISCHEMIA IMPAIRS VASODILATION IN SKELETAL MUSCLE RESISTANCE ARTERY." DigitalCommons@CalPoly, 2011. https://digitalcommons.calpoly.edu/theses/546.

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Functional vasodilation in arterioles is impaired with chronic ischemia. We sought to examine the impact of chronic ischemia and age on skeletal muscle resistance artery function. To examine the impact of chronic ischemia, the femoral artery was resected from young (2-3mo) and adult (6-7mo) mice and the profunda femoris artery diameter was measured at rest and following gracilis muscle contraction 14 days later using intravital microscopy. Functional vasodilation was significantly impaired in ischemic mice (14.4±4.6% vs. 137.8±14.3%, p<0.0001 n=8) and non-ischemic adult mice (103.0±9.4% vs. 137.8±14.3%, p=0.05 n=10). In order to analyze the cellular mechanisms of the impairment, a protocol was developed to apply pharmacological agents to the experimental preparation while maintaining tissue homeostasis. Endothelial and smooth muscle dependent vasodilation were impaired with ischemia, 39.6 ± 13.6% vs. 80.5 ± 11.4% and 43.0 ± 11.7% vs. 85.1 ± 10.5%, respectively. From this data, it can be supported that smooth muscle dysfunction is the reason for the observed impairment in arterial vasodilation.

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Leitner, Lucia Maria [Verfasser], Axel [Gutachter] Gödecke, Ulrich [Gutachter] Rüther, and Axel [Akademischer Betreuer] Gödecke. "Heart Failure rapidly induces Wasting-related Program in Skeletal Muscle / Lucia Maria Leitner ; Gutachter: Axel Gödecke, Ulrich Rüther ; Betreuer: Axel Gödecke." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/1163804681/34.

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30

Hawash, Ahmed Alaa. "Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita." Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright1500932300888521.

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31

Garfield, Ben. "Growth and differentiation factor 15 causes skeletal muscle wasting in pulmonary arterial hypertension through actions on transforming growth factor β activated kinase 1." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/59682.

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Muscle wasting is an important complication of a wide range chronic diseases. Pulmonary arterial hypertension (PAH) is no different. Novel targets and treatments are required to help improve outcomes in patients with PAH complicated by muscle wasting. GDF-15 is prognostic marker in PAH and has been shown to cause muscle wasting in vitro and in vivo. The pathway through which GDF-15 acts in muscle cells is not established. I used a human study, animal models of PAH; the monocrotaline (MCT) rat; and Sugen/hypoxia mouse, as well as C2C12 muscle cells to determine whether GDF-15 and its downstream signals may be important in the development of muscle wasting and low physical activity in PAH. Muscle wasting and low physical activity were associated with poor outcomes in a population of patients with PAH. Circulating GDF-15 levels were associated with markers of muscle strength and size in 2 animal models and in patients with PAH. In the MCT rat the pulmonary vasculature was an important site of production of GDF-15. GDF-15 acted by increasing the expression of ubiquitin ligases, which are involved in muscle wasting. GDF-15 decreased the activity of SMAD 1, 5 whilst increasing transforming growth factor β activated kinase 1 (TAK1) phosphorylation in muscle cells. Antagonising TAK1 with 5(Z)-7-oxozeaenol partially prevented muscle loss and rises in ubiquitin ligase expression in muscle cells and prevented weight loss in some MCT rats treated for 9 days with the drug. Muscle wasting and low physical activity are potentially modifiable risk factors for poor prognosis in PAH. GDF-15 may be a useful biomarker of muscle loss in PAH. Antagonising GDF-15 through its downstream mediator TAK1 requires further evaluation in animal models and patients with PAH to establish its usefulness in clinical practice.

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32

McLean, Julie B. "Tumor-derived proteins and mitochondrial dysfunction in lung cancer-induced cachexia." UKnowledge, 2015. http://uknowledge.uky.edu/physiology_etds/21.

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Lung tumors secrete multiple factors that contribute to cachexia, a severe wasting syndrome that includes loss of muscle mass, weakness, and fatigue. 80% of advanced lung cancer patients experience cachexia, which cannot be reversed by nutritional interventions, diminishes response to and tolerance of cancer treatments, and increases morbidity and mortality. Despite a multitude of clinical trials, there are currently no approved treatments. This deficiency suggests that not all of the factors that contribute to cachexia have been identified. Cancer is frequently accompanied by an increase in cyclooxygenase-2 (COX-2), a hallmark of inflammation. Clinical trials for COX-2 inhibitors have resulted in restoration of muscle mass and decreased fatigue. Along with loss of myofibrillar proteins, cachexia also induces mitochondrial dysfunction, which contributes to fatigue. The amelioration of fatigue by COX-2 inhibition suggests possible alterations to mitochondrial function. We hypothesized that there were unidentified tumor-derived factors that contribute to cachectic wasting and fatigue. Treatment of C2C12 myotubes with Lewis lung cancer-conditioned media (LCM) resulted in increased COX-2 content, myosin loss, and mitochondrial dysfunction. Mass spectrometry revealed 158 confirmed proteins in LCM. We focused on extracellular 14-3-3 proteins because they bind and regulate over 200 known partners. We found that depletion of extracellular 14-3-3 proteins diminished myosin content. CD13, an aminopeptidase, is the proposed receptor for 14-3-3 proteins. Inhibiting aminopeptidases with Bestatin also reduced myosin content. LCM treatment decreased basal and ATP-related mitochondrial respiration, caused a transient rise in reactive oxygen species (ROS), and increased 4-Hydroxynonenal (4-HNE) in both cytosolic and mitochondrial fractions of cell lysates. COX-2 inhibition did not spare myosin content in LCM-treated myotubes, but did alter mitochondrial respiration and cytosolic oxidant levels. Our novel findings show that extracellular 14-3-3 proteins may act as previously unidentified myokines, signaling via aminopeptidases to help maintain muscle mass. We elucidated how LCM alters mitochondrial electron flow, and increases oxidative damage by ROS and 4-HNE. Although successful in clinical trials, COX-2 inhibitors do not appear to spare muscle mass by directly working on skeletal muscle, but did alter mitochondrial function.

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33

Rocha, Mariana Frota Cúcio De Moraes. "A novel assay to measure mitochondrial dysfunction in human skeletal muscle : implications for the diagnosis and treatment of mitochondrial diseases." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3255.

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Mitochondrial dysfunction occurs in patients with mitochondrial disease, in neurodegenerative conditions and as part of the ageing process. It affects predominantly tissues with high metabolic requirements such as central nervous system and skeletal muscle. In patients with mitochondrial disease, both mitochondrial and nuclear genetic defects commonly cause a biochemical defect in muscle. However, due to the multi-copy nature of mitochondrial DNA, muscle displays a mosaic pattern of deficiency when the mitochondrial genome is affected. This particular pattern makes these defects challenging to quantify. Current standard methods to diagnose and investigate mitochondrial disease in affected tissues present several limitations. Biochemical studies are only suitable for cases with a high proportion of cells with mitochondrial respiratory chain deficiency. Moreover, histochemical assays only provide qualitative assessment of complex II and IV activities and are not capable of evaluating other complexes, such as complex I - the commonest affected respiratory complex in mitochondrial pathology. This project aimed therefore at developing a novel assay to accurately quantify mitochondrial dysfunction in human skeletal muscle. Once optimised, this assay was further used to explore: the mechanisms underlying mitochondrial pathology, its potential in helping the current diagnostic setting, as well as its potential to assess the effectiveness of therapeutic approaches aimed at treating mitochondrial dysfunction. This work described the development and validation of a novel quadruple immunofluorescent technique. This assay quantifies accurately key subunits of respiratory complexes I and IV together with mitochondrial mass, using a single 10μm section. The additional labelling of a cell membrane marker allows semi-automatic and computer-based sampling of large numbers of individual muscle fibres. Using this technique, this study characterised a variety of mitochondrial and nuclear genetic defects and demonstrated that specific genotypes exhibit distinct biochemical signatures in muscle. In patients with suspected mitochondrial disease, this assay provided clues on the possible genetic causes. Furthermore, this novel assay evaluated the effect of an endurance exercise program in patients with mitochondrial myopathy and was able to detect subtle changes in respiratory complexes levels.

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Martin, Agnès. "Role of the glucocorticoid pathway in skeletal muscle wasting and hepatic metabolism rewiring during cancer cachexia in ApcMin/+ mice – Functional implication of myostatin gene invalidation." Thesis, Lyon, 2020. http://www.theses.fr/2020LYSES034.

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La cachexie affecte environ la moitié des patients atteints d’un cancer et est caractérisée par une perte progressive de la masse corporelle résultant principalement d’une perte de masse musculaire squelettique. Cette perte de masse musculaire squelettique associée à une perte de force musculaire contribue fortement à réduire la qualité de vie des patients, l’efficacité des traitements et à terme, la survie des patients. Plusieurs facteurs sont connus pour être impliqués dans la régulation de la masse musculaire. Parmi eux, les glucocorticoïdes sont des hormones stéroïdiennes sécrétées sous le contrôle de l’axe hypothalamo-hypophysaire qui sont connues pour induire l’atrophie musculaire mais aussi pour avoir une action systémique via l’activation ou l’expression de gènes dans plusieurs tissus. Nous faisons l’hypothèse que la voie des glucocorticoïdes pourrait être activée pendant la cachexie associée au cancer dans les souris ApcMin/+, un model murin de cancer intestinal. Nous rapportons ici que l’activation du catabolisme musculaire était associée à une reprogrammation complète du métabolisme du foie. En outre, nous montrons une activation de l’axe hypothalamo-hypophysaire associée à une augmentation du niveau en corticostérone (le glucocorticoïde principal chez les rongeurs) dans le sérum, le muscle quadriceps et le foie des souris à un stade avancé de la cachexie associée au cancer. La signature transcriptionnelle dans le muscle quadriceps et le foie des souris à un stade avancé de la cachexie associée au cancer reflète celle observée dans des souris traitées avec de la dexaméthasone, un analogue des glucocorticoïdes. Il est important de souligner que l’inhibition de la cachexie associée au cancer par l’inactivation du gène de la myostatine dans les souris ApcMin/+ a restauré les niveaux en corticostérone et abolit la reprogrammation génique dans le muscle squelettique et le foie. Ensemble, ces données indiquent que les glucocorticoïdes induisent un programme transcriptionnel pour réguler de façon coordonnée la perte de masse musculaire et le remaniement du métabolisme hépatique. L’inhibition de cette réponse par l’invalidation du gène de la myostatine souligne l’existence d’un dialogue moléculaire entre le muscle squelettique et le foie
Cachexia affects about half of cancer patients and is characterized by a progressive body mass loss mainly resulting from skeletal muscle depletion. This loss of skeletal muscle mass together with a decrease in muscle force strongly contribute to reduce cancer patient quality of life, treatment efficiency and ultimately patient survival. Many factors are known to be involved in the regulation of skeletal muscle homeostasis. Among them, glucocorticoids are steroid hormones secreted under the control of the hypothalamic-pituitary axis that have been well described to promote skeletal muscle atrophy but also to exert systemic actions through activation or repression of gene expression in many tissues. We hypothesized that the glucocorticoid pathway could be activated during cancer cachexia in ApcMin/+ mice, a mouse model of intestinal cancer. Here, we reported that activation of skeletal muscle catabolism was associated with a complete reprogramming of liver metabolism. Moreover, we showed an activation of the hypothalamus-pituitary axis that was associated with an increase in the level of corticosterone (the main glucocorticoid in rodent) in serum, quadriceps muscle and liver of advanced cancer cachectic mice. The transcriptional signature in quadriceps muscle and liver of advanced cancer cachectic mice significantly mirrored that observed in mice treated with dexamethasone, an analog glucocorticoid. Importantly, the inhibition of cancer cachexia by myostatin gene invalidation in ApcMin/+ mice restored corticosterone levels and abolished skeletal muscle and liver gene reprogramming. Together, these data indicate that glucocorticoids drive a transcriptional program to coordinately regulate skeletal muscle mass loss and hepatic metabolism rewiring. The inhibition of this response by myostatin gene invalidation highlights the existence of a molecular dialog between skeletal muscle and liver

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Lima, Tãnia Marisa da Costa. "Molecular and functional changes in cardiac and skeletal muscle in HFpEF remodelling and reverse remodelling." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22238.

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Mestrado em Bioquímica
A insuficiência cardíaca (IC) com fração de ejeção preservada (ICFEp) é uma síndrome com uma etiologia muito diversificada, cuja disfunção metabólica tem sido apontada como um importante mecanismo associado à sua severidade. A remodelagem do miocárdio, resulta de uma agressão ao coração que pode ser direta (isquemia, estenose aórtica, etc) ou indireta (diabetes, disfunção renal, etc). Quando esta agressão é atenuada, por tratamento farmacológico ou cirúrgico, o coração sofre uma remodelagem reversa (RR) e o miocárdio retoma à sua estrutura e função normais. Conhecer os mecanismos subjacentes ao padrão de remodelagem e RR do miocárdio irá certamente potenciar novas oportunidades de tratamento da ICFEp. Por ser uma síndrome multisistémica, os doentes com ICFEp apresentam frequentemente sinais e sintomas extra-cardíacos característicos do diagnóstico desta patologia, como é o caso da intolerância ao esforço. Assim este trabalho teve como objetivos implementar e caracterizar um modelo animal de ICFEp, bem como avaliar as alterações estruturais, funcionais e moleculares que ocorrem ao nível do músculo cardíaco e esquelético na remodelagem e RR. Os nossos resultados mostram que a implementação de um modelo animal que mimetiza o fenótipo de ICFEp foi bem-sucedida. De facto, os animais banding apresentaram uma marcada hipertrofia do ventrículo esquerdo (VE), disfunção diastólica com rigidez do miocárdio, alterações na regulação do cálcio e aumento do stress oxidativo. Observaram-se ainda alterações que sugerem um aumento da biogénese e da fissão mitocondrial bem como um aumento dos transportadores de glucose. Apesar do aumento da expressão da proteína desacopladora 1 (UCP-1), funcionalmente, as mitocôndrias apresentaram uma melhoria da sua função. A redução da performance física dos animais banding foi acompanhada de alterações estruturais ao nível do músculo-esquelético, assim como de uma alteração dos transportadores dos substratos metabólicos. Curiosamente, nos animais debanding, apesar da recuperação funcional, morfologicamente o miocárdio não normalizou totalmente. Adicionalmente, observou-se um aumento dos transportadores de ácidos gordos, acompanhado por uma diminuição do stress oxidativo e da apoptose no VE. Além disso, apesar da melhoria metabólica, as mitocôndrias do VE dos animais debanding mantém-se menores. Relativamente à capacidade aeróbica dos animais, observou-se uma melhoria após o debanding acompanhada por uma reversão da atrofia e a fibrose das fibras musculares, assim como da oxidação dos ácidos gordos. Este trabalho mostra evidências do envolvimento mitocondrial e metabólico na progressão da ICFEp, ao nível dos músculo-esquelético e cardíaco.
Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a diverse aetiology in which the metabolic dysfunction has been pointed out as an important mechanism that underlies the disease severity. Myocardial remodelling results from cardiac injury that can be direct (ischemia, aortic stenosis, etc) or indirect (diabetes, renal dysfunction, etc). When the deleterious stimulus is attenuated by pharmacological or surgical treatment, the heart enrols in a process called reverse remodelling (RR), and myocardial structure and function returns to normal. The knowledge of the molecular mechanism that underlie the RR process could represent an opportunity to develop novel therapeutic approaches and thus improve the treatment of HFpEF patients. As being a multi-systemic syndrome, HFpEF presents several extra-cardiac signals and symptoms typical of its diagnosis, such as effort intolerance. Thus, the aims of this work was to implement and characterize an animal model of cardiac remodelling and reverse remodelling of HFpEF and thus characterize structurally, functionally and molecularly the changes that occurs at the myocardium and at the skeletal muscle. Our results showed that we successfully implemented an animal model of HFpEF that presents an LV hypertrophic and increased stiffness. Additionally to LV diastolic dysfunction (DD) we also observed abnormalities on calcium and oxidative stress. In banding rats we denoted an increase of peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1α) and downregulation of mitofusin (MNF1,2) as well as an augment of glucose transporters. Despite de increase of uncoupled protein 1 (UCP-1) expression, functionally we denoted an improvement of mitochondria respiration and membrane potential. The physical performance of banding animals was impaired and accomplished by structural changes at skeletal muscle level as well as at metabolic substrate transporters. Curiously, after afterload relief despite the functionally recovery, morphologically the myocardial reverse remodelling was incomplete. Moreover, regardless the metabolic transporters reversion the mitochondria continue smaller. After overload relief the rats showed an improvement on aerobic capacity as well as a reversion on skeletal muscle atrophy, fibrosis and an upregulation of FA oxidation. The present study shows clearly the involvement of mitochondria and metabolism on myocardial and skeletal muscle remodelling and RR.

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Houghton, Michael James. "The chronic effects of dietary (poly)phenols on mitochondrial dysfunction and glucose uptake in cellular models of the liver and skeletal muscle." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/20631/.

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Background: Type 2 diabetes is characterised by chronic hyperglycaemia, insulin resistance and associated mitochondrial dysfunction. (Poly)phenols have been shown to attenuate cellular oxidative stress and restore glucose homeostasis, but the specific mechanisms and compounds responsible remain unknown. Methods: HepG2 cells were used as an in vitro hepatic model, on which the effects of quercetin on high glucose-induced oxidative stress and mitochondrial dysfunction were investigated. Mitochondria were assessed for complex I activity, cellular redox status, mitochondrial respiration and PGC-1α expression. LHCN-M2 human skeletal myocytes were differentiated in various glucose and insulin concentrations and characterised for their use as a model to explore the effects of relevant (poly)phenol metabolites on glucose uptake and metabolism. Metabolic phenotype and the effects of metabolites derived from ferulic acid, flavonols, resveratrol and berry (poly)phenols were evaluated by Western capillary protein assays, uptake of 2-[1-14C(U)]-deoxy-D-glucose and D-[14C(U)]-glucose; respirometry and the ROS assay were also used for initial metabolic characterisation. Results: Mitochondrial function was restored by quercetin in HepG2 cells exposed to high glucose, by reversing the increased cellular NADH, enhancing mitochondrial respiration and preventing proton leak, and upregulating PGC-1α, all of which led to restored complex I activity after 24 h. The LHCN-M2 model was established and cells differentiated in a normal or high glucose/insulin environment. Glucose transport was restored, and metabolism increased, in high glucose/insulin myotubes by various metabolites. Isovanillic acid 3-O-sulfate in particular elicited this effect by upregulating GLUT1, GLUT4 and PI3K protein expression, and acutely activating the insulin signalling pathway. Conclusions: Quercetin protects against hepatic mitochondrial dysfunction through pleiotropic effects involving improved redox status and enhanced mitochondrial respiration and function. (Poly)phenol metabolites, including the gut microbiome catabolite isovanillic acid 3-O-sulfate, restore glucose uptake and metabolism in human skeletal muscle exposed to high glucose and insulin, via insulin-dependent pathways.

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Damatto, Ricardo Luiz [UNESP]. "Caracterização morfológica, bioquímica e molecular do músculo esquelético sóleo de ratos espontaneamente hipertensos com insuficiência cardíaca." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/92160.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A insuficiência cardíaca (IC) caracteriza-se por redução da tolerância aos exercícios com a ocorrência precoce de fadiga e dispnéia. Além de disfunção cardíaca e pulmonar, anormalidades intrínsicas da musculatura esquelética têm sido responsabilizadas pela intolerância aos esforços físicos. Em músculos periféricos e respiratórios, frequentemente são observadas atrofia e modificação nas isoformas das cadeias pesadas de miosina (MyHC) na IC. Os mecanismos e vias intracelulares de sinalização responsáveis por essas alterações ainda não estão completamente definidos. Em modelos experimentais de IC induzida por estenose aórtica ou infarto do miocárdio, verificamos que alterações na expressão dos fatores de regulação miogênica e da via miostatina/folistatina podem modular o trofismo muscular e a composição das MyHCs. Um dos modelos experimentais muito utilizados para o estudo da IC é o rato espontaneamente hipertenso (SHR). Estes animais apresentam, precocemente, hipertensão arterial e hipertrofia ventricular esquerda e, em idade avançada, desenvolvem IC. Não identificamos estudos que avaliaram o comprometimento da musculatura esquelética de SHR com IC. O objetivo deste estudo foi caracterizar as alterações da musculatura esquelética de SHR com IC por meio de avaliação da morfologia, das isoformas das cadeias pesadas de miosina e da expressão gênica e protéica dos fatores de regulação miogênica e da via miostatina/folistatina. A partir de 18 meses de idade, ratos espontaneamente hipertensos foram avaliados duas vezes por semana à procura de evidências clínicas de IC como taquipnéia, perda de peso e apatia. Após a detecção de IC, os animais foram submetidos a ecocardiograma transtorácico para a confirmação de disfunção ventricular e eutanasiados. No momento da eutanásia, foram...
Heart failure (HF) is characterized by limited exercise tolerance due to increased muscle fatigue and impaired endurance. Besides cardiac and pulmonary dysfunction, intrinsic skeletal muscle abnormalities have been shown to be involved on reduced exercise tolerance. muscle mass loss and a shift in myosin heavy chain (MyHC) isoforms have been frequently observed in peripheral and respiratory skeletal muscles during HF. The pathophysiological mechanisms and intracellular pathways responsible for muscle changes are not completely defined. We observed that myogenic regulatory factors expression and myostation/follistatin pathway modulate muscle trophism and MyHC isoforms in experimental aortic stenosis- and myocardial infarction-induced HF. The spontaneously hypertensive rat (SHR) is often used in HF studies. These rats develop systemic arterial hypertension and left ventricular hypertrophy early and HF at 18-22 month-age approximately. To the best of our knowledgement, there is not study on skeletal muscle evaluation in SHR with HF. The aim of this study was to characterize skeletal myopathy of SHR with HF by evaluating soleus muscle morphology, MyHC isoforms, and gene and protein expression of myogenic regulatory factors, myostatin, and follistatin. Eighteen month-old spontaneously hypertensive rats were evaluated twice a week to identify HF clinical features such as taquipnea, weight loss, and apathy. After detecting HF, rats were subjected to transthoracic echocardiogram. During euthanasia, we evaluated pathological evidences of HF such as pleuropericardial effusion, ascites, left atrial thrombi, right ventricular hypertrophy, and lung congestion. Agematched Wistar-Kyoto rats used as controls. Soleus morphology was analyzed in haematoxyin and eosin and picro-sirius red stained sections, and MyHC isoforms were evaluated by protein... (Complete abstract click electronic access below)

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38

Damatto, Ricardo Luiz. "Caracterização morfológica, bioquímica e molecular do músculo esquelético sóleo de ratos espontaneamente hipertensos com insuficiência cardíaca /." Botucatu : [s.n.], 2010. http://hdl.handle.net/11449/92160.

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Resumo: A insuficiência cardíaca (IC) caracteriza-se por redução da tolerância aos exercícios com a ocorrência precoce de fadiga e dispnéia. Além de disfunção cardíaca e pulmonar, anormalidades intrínsicas da musculatura esquelética têm sido responsabilizadas pela intolerância aos esforços físicos. Em músculos periféricos e respiratórios, frequentemente são observadas atrofia e modificação nas isoformas das cadeias pesadas de miosina (MyHC) na IC. Os mecanismos e vias intracelulares de sinalização responsáveis por essas alterações ainda não estão completamente definidos. Em modelos experimentais de IC induzida por estenose aórtica ou infarto do miocárdio, verificamos que alterações na expressão dos fatores de regulação miogênica e da via miostatina/folistatina podem modular o trofismo muscular e a composição das MyHCs. Um dos modelos experimentais muito utilizados para o estudo da IC é o rato espontaneamente hipertenso (SHR). Estes animais apresentam, precocemente, hipertensão arterial e hipertrofia ventricular esquerda e, em idade avançada, desenvolvem IC. Não identificamos estudos que avaliaram o comprometimento da musculatura esquelética de SHR com IC. O objetivo deste estudo foi caracterizar as alterações da musculatura esquelética de SHR com IC por meio de avaliação da morfologia, das isoformas das cadeias pesadas de miosina e da expressão gênica e protéica dos fatores de regulação miogênica e da via miostatina/folistatina. A partir de 18 meses de idade, ratos espontaneamente hipertensos foram avaliados duas vezes por semana à procura de evidências clínicas de IC como taquipnéia, perda de peso e apatia. Após a detecção de IC, os animais foram submetidos a ecocardiograma transtorácico para a confirmação de disfunção ventricular e eutanasiados. No momento da eutanásia, foram... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Heart failure (HF) is characterized by limited exercise tolerance due to increased muscle fatigue and impaired endurance. Besides cardiac and pulmonary dysfunction, intrinsic skeletal muscle abnormalities have been shown to be involved on reduced exercise tolerance. muscle mass loss and a shift in myosin heavy chain (MyHC) isoforms have been frequently observed in peripheral and respiratory skeletal muscles during HF. The pathophysiological mechanisms and intracellular pathways responsible for muscle changes are not completely defined. We observed that myogenic regulatory factors expression and myostation/follistatin pathway modulate muscle trophism and MyHC isoforms in experimental aortic stenosis- and myocardial infarction-induced HF. The spontaneously hypertensive rat (SHR) is often used in HF studies. These rats develop systemic arterial hypertension and left ventricular hypertrophy early and HF at 18-22 month-age approximately. To the best of our knowledgement, there is not study on skeletal muscle evaluation in SHR with HF. The aim of this study was to characterize skeletal myopathy of SHR with HF by evaluating soleus muscle morphology, MyHC isoforms, and gene and protein expression of myogenic regulatory factors, myostatin, and follistatin. Eighteen month-old spontaneously hypertensive rats were evaluated twice a week to identify HF clinical features such as taquipnea, weight loss, and apathy. After detecting HF, rats were subjected to transthoracic echocardiogram. During euthanasia, we evaluated pathological evidences of HF such as pleuropericardial effusion, ascites, left atrial thrombi, right ventricular hypertrophy, and lung congestion. Agematched Wistar-Kyoto rats used as controls. Soleus morphology was analyzed in haematoxyin and eosin and picro-sirius red stained sections, and MyHC isoforms were evaluated by protein... (Complete abstract click electronic access below)
Orientador: Marina Politi Okoshi
Coorientador: Maeli Dal Pai Silva
Banca: Luiz Shiguero Matsubara
Banca: José Francisco Saraiva
Mestre

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39

Assi, Mohamad. "L'impact de l'activité physique et des antioxydants sur le dialogue entre la tumeur et le muscle squelettique dans le cancer : déchiffrage de voies de signalisation impliquées dans la croissance de la tumeur et l'atrophie musculaire." Thesis, Rennes 2, 2016. http://www.theses.fr/2016REN20055/document.

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Les espèces réactives de l’oxygène (ERO) contrôlent plusieurs aspects de la carcinogenèse, étant donné leur capacité àpromouvoir la prolifération mais aussi à induire la sénescence et l’apoptose. Dans les stades avancés de cancer, les EROpeuvent également participer au développement de l’atrophie musculaire, engendrant une détérioration de la qualité de viedes patients. L’activité physique (AP), connue pour augmenter les défenses antioxydants de l’organisme et lasupplémentation en antioxydants sont considérées comme deux stratégies susceptibles de moduler la croissance tumorale, d’améliorer la performance physique et de réduire les effets secondaires liés à la maladie et aux traitements anticancéreux. Néanmoins, plusieurs questions restent aujourd’hui sans réponse. En effet, bien que l’AP puisse réduire la progression du cancer du sein, du colon et de la prostate, son impact sur les cancers se développant au sein du muscle (ex : le liposarcome), donc soumis aux contractions musculaires répétées, reste méconnu. En utilisant des approches in vivo et in vitro, nous avons démontré que maintenir une AP régulière accélère la croissance du liposarcome intramusculaire, probablement, via la réduction des taux circulants d’insuline et l’inhibition de la voie « P38 MAPK-P21 ». Pour les patients ne pouvant pas pratiquer d’AP, la consommation d’antioxydants pourrait être un moyen de réduire les ERO tumorales et musculaires et ainsi être prometteuse. Toutefois, les études actuelles restent très controversées. Nos travaux ont montré dans un modèle murin de cachexie cancéreuse que des doses nutritionnelles d’un produit antioxydant commercialisé en France, étaient suffisantes pour accélérer la croissance de la tumeur colique, favoriser la perte de masse corporelle totale et musculaire et engendrer la mort prématurée des souris. L’ensemble de nos résultats suggère que la pratique d’AP et la consommation en antioxydants peuvent induire des effets différents selon le type de tumeur et leur implantation, nécessitant une prise en charge individualisée des patients. En effet, (1) les patients atteints d’un LS intramusculaire devraient éviter de pratiquer une AP durant la période préopératoire mais ces résultats doivent être confirmés par une étude clinique, (2) les patients avec un stade avancé de cancer devraient être vigilants quant à l’utilisation de suppléments antioxydants ; une telle pratique pouvant avoir des répercussions dangereuses sur leur santé
Reactive oxygen species (ROS) control several aspects of carcinogenesis as they can either promote tumor growth andprogression or senescence and apoptosis. In advanced stages of cancer, ROS can also drive the development of other cancerrelated complications like, muscle wasting. Physical activity (PA) and antioxidant supplementation have been proposed as two adjuvant strategies to better control tumor growth, ameliorate performance and alleviate secondary symptoms related to cancer itself or to the heavy anticancer therapies. However, several issues remain to be elucidated. First of all, although PA could reduce colon, breast and prostate cancer growth and progression, its impact remains unknown on orthotopic intramuscular tumors like liposarcoma, which directly affect the musculoskeletal apparatus and reduce physical function. Secondly, given the limitedness of PA application in some advanced stages of cancer, patients may increase their dependency on nutritional and antioxidant complements as an alternative strategy, but such practice has spark a lot of polemic and inconsistent results. In this thesis, we have addressed the effectiveness of PA and antioxidants in two distinct animal models of cancer. Using in vivo and in vitro approaches, we found that voluntary PA accelerated the growth of intramuscular liposarcoma tumors and exacerbated skeletal muscle dysfunction, mainly, by decreasing circulating insulin levels and the subsequent activation of the tumor suppressor pathway “P38 MAPK-P21”. We also demonstrated that nutritional doses of commercial antioxidants enhanced colon tumor growth, total body/skeletal muscle weight loss and caused premature death of mice. Such mechanism was due to selective changes in oxidative damage profiles, which decreased in tumor but increased in skeletal muscle, in a way driving tumor growth and skeletal muscle wasting/dysfunction. Clinically, it seems that (1) patients with intramuscular liposarcoma may, at least, not increase their levels of PA or undergo hospital-supervised exercise program, during the preoperative period; until the confirmation of our findings with clinical data and (2) patients with advanced stages of cancer must be very careful against the use of antioxidants as it could lifethreatening. Accordingly, health agencies in France, Europe and USA prohibit the use of synthetic antioxidant supplements without dietary counseling by a cancer patient’s physician and/or nutritionist

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Breda, Ana Paula. "Avaliação da musculatura estriada de membros inferiores na limitação funcional ao exercício em pacientes com hipertensão arterial pulmonar." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5150/tde-20072011-145309/.

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Introdução: A hipertensão arterial pulmonar (HAP) é uma doença progressiva extremamente grave, que evolui com insuficiência cardíaca direita e morte. Apesar do avanço do tratamento farmacológico, o prognóstico permanece reservado com taxa de sobrevida de 86%, 70% e 55% em 1, 3 e 5 anos, respectivamente. A dispnéia progressiva e a intolerância ao exercício são as principais manifestações clínicas e refletem a falência do ventrículo direito. O músculo esquelético periférico parece ser também um dos principais determinantes desta limitação funcional, visto que a redução da oferta de oxigênio e alterações na extração/utilização do oxigênio pelo músculo são diretamente relacionados com a tolerância ao exercício. Existem dois mecanismos potencialmente envolvidos na regulação da oferta de oxigênio, e portanto, na capacidade de exercício: mecanismos centrais (função do coração, pulmão e sistema nervoso autônomo) e mecanismos periféricos (associado ao fluxo sanguíneo periférico e a função do músculo esquelético). Os pacientes com HAP geralmente apresentam baixo débito cardíaco e estado adrenérgico exacerbado. A combinação destas alterações pode resultar em alterações estruturais e funcionais da musculatura estriada periférica. Porém, não existem informações sólidas que nos esclareçam se o acometimento muscular é preditor independente da limitação da capacidade de exercício. Objetivos: (1) Caracterizar o papel da musculatura periférica na limitação funcional em pacientes com HAP. (2) Avaliar o papel do sistema muscular periférico como um fator independente para a limitação ao exercício em HAP. Materiais e métodos: Dezesseis pacientes com HAP foram prospectivamente comparados com 10 indivíduos controle em termos de dados demográficos, qualidade de vida relacionada à saúde e limitação ao exercício, avaliada pelo teste de caminhada de seis minutos, teste cardiopulmonar, dinamometria isocinética e medições de pressão respiratória máxima. Pacientes com HAP também foram submetidos à biópsia do quadríceps, a fim de avaliar as mudanças estruturais. Resultados: Os pacientes com HAP apresentaram pior qualidade de vida (componente físico p<0,001), menor percentagem de massa magra (p=0,044), menor força muscular respiratória (p<0,001), menor resistência e força dos extensores de coxa (p=0,017 e p=0,012, respectivamente) e maior limitação funcional demonstrada pela distância percorrida no teste de caminhada de seis minutos (p<0,001) e pelo teste de exercício cardiopulmonar (p<0,001 para VO2/kg), em comparação ao grupo controle. Estes achados de redução de força e função muscular estão em acordo com os achados de redução da percentagem de fibras do Tipo I à biópsia muscular. O consumo de oxigênio, apresentou correlação com a função da musculatura respiratória e da musculatura extensora de coxa (resistência e força), e com a proporção de fibras oxidativas (Tipo I). O débito cardíaco também apresentou correlação com o VO2. o modelo de análise bivariada demonstrou que a função muscular é preditora independente do VO2 pico, mesmo com a correção para o perfil hemodinâmico. Conclusão: (1) Pacientes com HAP apresentam alteração estrutural e funcional da musculatura estriada periférica, e (2) estas alterações determinam limitação da capacidade global de exercício de forma independente do padrão hemodinâmico característico da HAP
Introduction: Pulmonary arterial hypertension (PAH) is a relentlessly progressive disease that leads to right heart failure and death. Despite advances in pharmacological treatment, prognosis is still poor with survival rates of 86%, 70% and 55% at 1, 3 and 5 years, respectively. Progressive dyspnea and exercise intolerance are the main clinical manifestations and reflect the impairment of right ventricular function. Peripheral skeletal muscle also seems to be a major determinant of functional limitation, as the reduction of oxygen supply and changes in extraction and utilization of oxygen by the muscle are directly associated to exercise tolerance. There are two potential mechanisms involved in the regulation of oxygen supply and therefore in exercise capacity: central (as a function of heart, lung and autonomic nervous system function) and peripheral (associated to peripheral blood flow and skeletal muscle function). Patients with PAH usually present low cardiac output and exacerbated adrenergic state. The combination of these features might result in changes of peripheral skeletal muscle and structure. However, there is no robust information that clearly clarifies whether the muscle involvement is an independent factor for exercise limitation. Objectives: (1) Characterize the role of the peripheral muscles in functional limitation in patients with PAH. (2) Address the role of the peripheral muscle system as an independent factor in exercise limitation in PAH. Materials and methods: Sixteen PAH patients were prospectively compared to 10 control individuals in terms of demographic data, health related quality of life and exercise limitation, assessed by six-minute walk test, cardiopulmonary test, isokinetic dynamometry and maximum respiratory pressure measurements. PAH patients also were submitted to vastus lateralis biopsy in order to assess structural changes. Results: PAH patients presented poorer quality of life (p <0.001), lower percentage of fat free mass (p = 0.044), lower respiratory muscle strength (p <0.001), lower resistance and strength of the extensor of the thigh (p = 0.017 and 0.012, respectively) and greater functional limitation demonstrated by the six-minute walk distance (p <0.001) and at the cardiopulmonary exercise test (p <0.001 for VO2max/kg), as compared to the control group. These findings of reduced muscle strength and function are in agreement with the findings of reduced percentage of Type I fibers at the muscle biopsy. The oxygen consumption correlated to the function of respiratory muscles and of extensor muscles of the thigh (endurance and strength) as well as to the proportion of oxidative fibers (Type I). The cardiac output also correlated with VO2. A bivariate model demonstrated that muscle function is an independent predictor of maximum oxygen consumption, even correcting for the hemodynamic profile. Conclusion: (1) PAH patients present functional and structural changes in peripheral skeletal muscles, and (2) these changes determine overall exercise capacity limitation, independently of the hemodynamic pattern

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Queiroz, André Lima. "O microRNA miR-696 regula a expressão da proteína PGC-1α e induz à disfunção mitocondrial em células musculares de camundongos através do sistema SNARK/miR-696/PGC-1&#945." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-30032017-162044/.

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A disfunção mitocondrial pode ser um mecanismo chave associado à ocorrência de doenças metabólicas como o diabetes. Neste contexto, é importante obeservar os mecanismos envolvidos nesse processo. MicroRNAs (miRs) são conhecidos por regular a expressão de genes em vários processos fisiológicos, incluindo o metabolismo de glicose e ácidos graxos, biogênese mitocondrial, proliferação, diferenciação e morte celular no músculo esquelético. Usando análise \"in silico\" (Sfold2.2) identificamos 219 microRNAs que, potencialmente, se ligam à região 3 \'UTR do PGC-1?, um gene envolvido na biogênese mitocondrial e no metabolismo de glicose. Dos 219 candidatos, encontramos um alto valor de energia livre de hibridização entre o microRNA miR-696 e PGC-1? (-29,8 kcal / mol), sugerindo que o miR-696 poderia estar envolvido na regulação negativa do PGC-1? resultando em disfunção mitocondrial. Consistente com esta hipótese, observamos que a expressão do miR-696 apresentou-se aumentada nos músculos esqueléticos de dois modelos de camundongos com diabetes: camundongos diabéticos induzidos por STZ e camundongos alimentados com dieta hiperlipídica. Para compreender se o miR-696 regula a disfunção mitocondrial utilizamos células musculares C2C12 expostas a uma alta dose de ácido palmítico (700 µM) durante 24 horas, o que causou uma redução na expressão de genes mitocondriais, bem como no consumo de oxigênio. Vale destacar que a inibição do miR-696 através da transfecção de oligonucleotídeos antisenso (ASO) preveniu, parcialmente, a perda da função mitocondrial de células C2C12 tratadas com ácido palmítico. Curiosamente, não houve nenhuma alteração nos níveis de miR-696 em modelos envolvidos com a proteína AMPK, tal como em células C2C12 incubadas com uma droga ativadora de AMPK (AICAR) e no músculo esquelético de camundongos transgênicos superexpressando AMPK?2 com o domínio quinase inativo ou AMPK?3 com mutação de ativação crônica (R70Q). Em contraste, a expressão alterada de uma quinase relacionadas com a AMPK, SNF1-AMPK-related kinase (SNARK), recentemente demonstrada por ter sua expressão aumentada em virtude do envelhecimento, exerceu efeitos significativos sobre a expressão do miR- 696, como por exemplo sua redução dependente do knockdown de SNARK em células C2C12. Consistente com estes resultados, a superexpressão de SNARK em células C2C12 resultou no aumento da expressão do miR-696 e redução na expressão do PGC-1?, bem como no consumo de oxigénio. Nossos resultados demonstram que o estresse metabólico aumenta a expressão do miR-696 no músculo esquelético, que por sua vez inibe a sinalização da PGC-1? e a função mitocondrial. Ainda, apesar da AMPK não se apresentar como mediadora da expressão do miR-696, SNARK pode desempenhar um papel neste processo através do mecanismo de sinalização SNARKmiR-696-PGC-1?.
Mitochondrial dysfunction may be a key underlying mechanism for occurrence of metabolic disease and diabetes; thus elucidating how this process occurs is of great value. MicroRNAs (miRs) are known to regulate gene expression in several physiological processes including metabolism, mitochondrial biogenesis, proliferation, differentiation and cell death in multiple tissues including adipose tissue and skeletal muscle. Using \"in silico\" analysis (Sfold2.2) we identified 219 unique microRNAs that potentially bind to the 3\'UTR region of PGC-1?, a gene involved in mitochondrial biogenesis and glucose metabolism. Out of the 219 candidates, there was a high value of hybridization free energy between the microRNA miR-696 and PGC-1? (- 29.8 kcal/mol), suggesting that miR-696 could be involved in the downregulation of PGC-1?, which in turn could cause mitochondrial dysfunction. Consistent with this hypothesis we found that miR-696 expression was increased in the skeletal muscles of two mouse models of diabetes that have impaired mitochondrial function: STZ-induced diabetic mice and chronic high fat fed mice. To understand if miR-696 regulates mitochondrial dysfunction we used C2C12 muscle cells exposed to a high dose of palmitic acid (700 µM) for 24 hours, which caused a decrease in mitochondrial gene expression and in oxygen consumption. Importantly, inhibition of miR-696 using an antisense oligo approach rescued the mitochondrial function by restoration of mitochondrial-related genes and increased oxygen consumption in the palmitic acid-treated C2C12 cells. Interestingly, there was no change in miR-696 levels in models involved with AMPactivated protein kinase such as C2C12 cells incubated with AICAR, skeletal muscle from AMPK?2 dominant-negative transgenic mice, and transgenic mice overexpressing the activating R70Q AMPK mutation. In contrast, altered expression of the AMPK-related kinase, SNF1- AMPK-related kinase (SNARK), recently shown to increase with aging, had significant effects on miR-696 expression. Knockdown of SNARK in C2C12 cells significantly decreased miR-696. Consistent with these findings, SNARK overexpression in C2C12 cells increased miR-696 concomitant with a decrease in PGC-1? expression and decreased oxygen consumption. Our findings demonstrate that metabolic stress increases miR-696 expression in skeletal muscle which in turn inhibits PGC-1? signaling and mitochondrial function. While AMPK does not mediate miR-696 expression, SNARK may play a role in this process through a SNARK-miR- 696-PGC-1? signaling mechanism.

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Hovhannisyan, Yeranuhi. "Modélisation cardiaque des myopathies myofibrillaires à l'aide de cellules souches pluripotentes induites pour explorer la pathogenèse cardiaque Polyacrylamide Hydrogels with Rigidity-Independent Surface Chemistry Show Limited Long-Term Maintenance of Pluripotency of Human Induced Pluripotent Stem Cells on Soft Substrates Modéliser la myopathie myofibrillaire pour élucider la pathogenèse cardiaque Synemin-related skeletal and cardiac myopathies: an overview of pathogenic variants Desmin prevents muscle wasting, exaggerated weakness and fragility, and fatigue in dystrophic mdx mouse Effects of the selective inhibition of proteasome caspase-like activity by CLi a derivative of nor-cerpegin in dystrophic mdx mice." Thesis, Sorbonne université, 2020. http://www.theses.fr/2020SORUS095.

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La myopathie myofibrillaire est une maladie neuromusculaire à évolution lente caractérisée par de graves troubles musculaires causés par des mutations dans le gène codant pour des protéines du cytosquelette. L'un des gènes affectés en relation avec le développement de la MFM est DES. Des mutations dans le gène de la desmine entraînent des myopathies des muscles squelettiques et cardiaques. Cependant, les évènements qu'elles entraînent et qui sont à l’origine des phénotypes pathologiques cardiaques restent mal connus. Mon objectif est de créer un modèle in vitro de MFM basé sur des cellules souches pluripotentes humaines afin d'étudier le rôle des mutations spécifiques dans la desmine sur le développement et la fonction des cellules cardiaques. Pour atteindre cet objectif, en collaboration avec les docteurs A. Behin, K. Wahbi et la société Phenocell, nous avons généré des iPSC à partir des cellules sanguines périphériques de patients souffrant d'une forme de cardiomyopathie induite par une mutation de la desmine. Les lignées iPSC générées contenant les mutations du gène codant la desmine ont permis d’étudier le rôle d’une mutation dans la spécification et la fonction des cardiomyocytes. La bioénergétique mitochondriale, la structure cellulaire et la fonction contractiles ont été évaluées au niveau cellulaire. En conclusion, il convient de noter que les mutations de la desmine conduisent à une désorganisation des structures des sarcomères dans les cardiomyocytes et à une perturbation de l'expression des protéines mitochondriales. Ce qui conduit à une altération des fonctions de la mitochondrie. Ces données permettent d’améliorer notre compréhension des mécanismes moléculaire qui sous-tendent le développement de la MFM
Myofibrillar Myopathy is a slowly progressive neuromuscular disease characterized by severe muscular disorders caused by mutations in the gene encoded cytoskeletal proteins. One of the genes described in connection with the development of MFM is DES. Mutations in the desmin gene lead to skeletal and cardiac muscles myopathies. However, the cardiac pathological consequences caused by them remain poorly understood. My objective is to create an in vitro human stem cell model of MFM to specifically investigate the role of patient-specific mutations in desmin on cardiac lineage development and function. To achieve that objective, in collaboration with Drs. Behin and K. Wahbi and Phenocell, we generate patient-specific iPSC from peripheral blood cells of the patient suffering severel form of desmin-deficient cardiomyopathy. The generated iPSC lines carrying DES gene mutations enable a powerful examination of the role of desmin mutation on cardiomyocyte specification and function. Bioenergetic, structural, and contractile function will be assessed in a single cell. In conclusion, it should be noted that desmin mutations lead to a disorganization of sarcomere structures in cardiomyocytes and to a perturbation of mitochondrial protein expression. This leads to a distortion of functions in the mitochondria. These data facilitate the understanding of the molecular pathway underlying the development of desmin-related myopathy. And the system we have created could also allow us to better evaluate the correlation between the desmin genotype and phenotype in terms of effect on the heart

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Guerci, Philippe. "Current and new therapies for the critically injured microcirculation The macro- and microcirculation of the kidney Endothelial dysfunction of the kidney in sepsis. Section 15: Infectious Diseases and Sepsis, Chapter 89 Impact of fluid resuscitation with hypertonic-hydroxyethyl starch versus lactated ringer on hemorheology and microcirculation in hemorrhagic shock Glycocalyx Degradation Is Independent of Vascular Barrier Permeability Increase in Nontraumatic Hemorrhagic Shock in Rats Glycocalyx shedding during stepwise hemodilution and microvascular permeability A LED-based phosphorimeter for measurement of microcirculatory oxygen pressure The role of bicarbonate precursors in balanced fluids during haemorrhagic shock with and without compromised liver function Effects of N-acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia Effect of Polyethylene-glycolated Carboxyhemoglobin on Renal Microcirculation in a Rat Model of Hemorrhagic Shock Resuscitation with PEGylated carboxyhemoglobin preserves renal cortical oxygenation and improves skeletal muscle microcirculatory flow during endotoxemia." Thesis, Université de Lorraine, 2020. http://www.theses.fr/2020LORR0053.

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Au cours des 20 dernières années, la microcirculation a été considérée comme la pierre angulaire du développement de la défaillance d’organe chez les patients critiques. De toute évidence, la microcirculation est devenue une cible thérapeutique. En raison de la complexité de la microarchitecture de ce système fonctionnel, variant d'un organe à l'autre, une thérapie ne peut pas «convenir pour tout». Les altérations observées dans la microcirculation sevèrement endommagée sont de 3 ordres: (i) le contenant défini par les différentes couches de la paroi vasculaire, y compris les cellules endothéliales et un gel protecteur appelé glycocalyx répandu à la surface, où le contact avec le sang est établi, (ii) le contenu représentant le plasma qui coule avec les différents éléments figures du sang et (iii) les tissus extraluminaux environnants. La microcirculation peut être endommagée de diverses manières, avec différents niveaux de dommage à ces éléments constitutifs. Ainsi, pour réanimer de manière appropriée la microcirculation lésée, le choix de la thérapie optimale ou du faisceau de thérapies doit être rationalisé avec une analyse méticuleuse des dommages subis par la microcirculation. Ainsi, l'évaluation de la microcirculation doit être obligatoirement multivariée. Dans cette thèse, la recherche s'est principalement concentrée sur un organe, le rein. La première partie est consacrée à la revue des mécanismes structurels et fonctionnels de la microcirculation rénale en condition physiologique et également septique. La deuxième partie tente d'identifier les rôles respectifs de chacun des composants de la microcirculation dans des conditions critiques notamment le glycocalyx et la viscosité du plasma. La perméabilité de la barrière vasculaire a été étudiée dans les modèles de choc hémorragique et d'hémodilution chez les rongeurs. Les principaux résultats suggèrent qu'il existe une gradation du niveau de lésion de la barrière vasculaire. La dernière partie de la thèse a examiné comment les thérapies actuelles et anciennes peuvent moduler la microcirculation en termes d'oxygénation, d'inflammation et de flux microcirculatoire dans le rein. Parmi les thérapies étudiées, la N-acétylcystéine était efficace pour limiter l'inflammation et augmenter l'oxygénation dans le rein. Une nouvelle génération de transporteur d'oxygène à base d'hémoglobine a montré une certaine efficacité dans le modèle endotoxémique murin. Dans l'ensemble, ces différents résultats se rejoignent pour montrer l'importance d'avoir une analyse multivariée de la microcirculation, car chacune des thérapies agit sur un aspect spécifique de celle-ci. Nous espérons que les résultats de cette recherche ouvrent la voie à une médecine plus personnalisée pour les patients
For the past 20 years, the microcirculation has been regarded as cornerstone in the development of organ failure in critically ill patients. Eventually, the microcirculation became a therapeutic target. Due to the complexity of the microarchitecture of this functional system, varying across organs, one therapy cannot “fit all”. The alterations observed in the critically injured microcirculation involve: (i) the container defined by the different layers of the vascular wall including the endothelial cells and a protective gel called the glycocalyx spread on the surface, where contact with blood is made, (ii) the contents representing the flowing plasma and the different elements of blood and (iii) the extraluminal surrounding tissue. The microcirculation can be injured in various ways, with different levels of injury to these constitutive elements. Thus, to appropriately resuscitate the injured microcirculation, the choice of the optimal therapy or bundle of therapies should be rationalized with a meticulous analysis of the damages suffered by the microcirculation. The evaluation of the microcirculation should be multivariate. In this thesis, the research was mainly focused on the kidney. The first part is dedicated to the review of the structural and functional mechanisms of the renal microcirculation in both healthy and septic states. The second part tries to identify the respective roles of each of the components of the microcirculation in critical conditions especially the glycocalyx and plasma viscosity. The vascular barrier permeability was investigated in hemorrhagic shock and hemodilution models in rodents. The main findings suggest that a gradation in the level of injury to the vascular barrier permeability exist.The last part of the thesis investigated how current and older therapies can modulate microcirculation in terms of oxygenation, inflammation and microcirculatory flow within the kidney. Among therapies investigated, N-acetylcysteine was efficient at limiting inflammation and increasing oxygenation within the kidney. A new generation of hemoglobin-based oxygen carrier showed some efficacy in murine endotoxemic model. Overall, these different findings coalesce to show the importance of having a multivariate analysis of the microcirculation, as each of the therapies acts on a specific aspect of it. Hopefully, this research helped pave the way for a more personalized medicine for the patients

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Sorensen, James. "Therapeutic Efficacy of a Co-Q10 Analogue in Combating Cachexia and Mortality Induced by Gold-Standard Paediatric Chemotherapy Regimens." Thesis, 2020. https://vuir.vu.edu.au/41826/.

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Chemotherapy is an effective first-line treatment against cancer; however, it induces a myriad of serious sequalae, including skeletal muscle dysfunction and wasting (SMDW) and fatigue, which we hypothesise is underpinned by mitochondrial dysfunction. When chemotherapy-induced (CI) SMDW is instigated in childhood, it often endures and manifests over the lifespan resulting in exacerbated morbidity and, in some cases, mortality. Despite much research having investigated individual chemotherapeutic agents and their effect on the skeletal muscle in mice (including our own), these models failed to evaluate the potential interactions between agents in a poly-pharmaceutical regimen, or, the effects of long-term and multi-staged chemotherapy regimens like that used in hospitals world-wide. Therefore, this thesis investigated the impact that gold-standard chemotherapy regimens used to combat the three common childhood cancers: acute lymphoblastic leukaemia (ALL), non- Hodgkin’s Burkitt lymphoma (NHBL) and medulloblastoma, on the skeletal muscle system in healthy juvenile mice and monitored the effects of treatment endured over the lifespan. After establishing pre-clinical animal models for three gold-standard chemotherapy regimens, we showed that, regardless of regimen, eight weeks of treatment to four-week-old mice induced considerable skeletal muscle dysfunction which was characterised by significant muscle weakness, fatigability and, in 2 of the 3 regimens, lean mass loss. Although the age of onset of these sequalae were variable (varying between eight-weeks and 30-weeks of life), mitochondrial dysfunction was evident, identifying a point for therapeutic intervention. As such, we investigated the efficacy of daily Idebenone treatment (a powerful antioxidant and mitochondrial Co-Q10 analogue) against mitochondrial dysfunction and thus CI-SMDW. Idebenone co-therapy greatly improved mitochondrial performance in chemotherapy- treated mice, as well as protecting against lean mass loss and improving overall strength in the more aggressive chemotherapy regimen used against NHBL. Moreover, Idebenone co- therapy was shown to completely abate chemotherapy-induced mortality in the NHBL regimen, reducing mortality from 77% to zero. This thesis shows that childhood chemotherapy, regardless of the aggressiveness of the regimen or the classes of drugs used, induces life-long SMDW which is likely contributed to by mitochondrial dysfunction. The mitochondrial targeting therapeutic, Idebenone, shows promising potential for clinical application against the SMDW sequalae and mortality induced by some regimens, with the potential to improve childhood chemotherapy patient outcomes and survivability.

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Liang, Tiffany. "GDF11 mediates cardiac and skeletal muscle dysfunction and cachexia." 2016. http://hdl.handle.net/1805/11074.

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Indiana University-Purdue University Indianapolis (IUPUI)
Growth differentiation factor 11 (GDF11) is important in regulating early fetal development of the axial skeleton and various visceral organs. Its actions on the adult body are less clear, and recent studies have led to conflicting accounts of GDF11’s ability to affect cardiac hypertrophy and skeletal muscle regeneration. If boosting GDF11 levels in adults had the ability to rejuvenate tissues and reverse the effects of aging, then the therapeutic possibilities are potentially vast. We attempted to provide clarification of this controversial topic by studying the effects of supraphysiologic levels of GDF11 in a mouse model using injected Chinese hamster ovary cells producing GDF11. We found that increasing endogenous levels of GDF11 in this in vivo mouse model resulted in overall bodily wasting, specifically with evidence of cardiac and skeletal muscle atrophy. In light of these results, caution must be exercised if GDF11 is ever considered as a potential therapeutic agent.

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Lee, Connie M. "Characterization of age-associated mitochondrial dysfunction in mammalian skeletal muscle." 1996. http://catalog.hathitrust.org/api/volumes/oclc/36335061.html.

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1996.
Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 111-132).

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Long, Gary Marshall. "Beet-ing Muscle Dysfunction and Exercise Intolerance in Pulmonary Hypertension." Diss., 2019. http://hdl.handle.net/1805/21334.

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Indiana University-Purdue University Indianapolis (IUPUI)
Background: Pulmonary Hypertension (PH) is a devastating disease characterized by pulmonary arterial remodeling, right ventricular dysfunction and ultimately right heart failure. Increased emphasis has been given to skeletal muscle dysfunction in PH, and to its implication in the severe exercise intolerance that is a hallmark of the condition. In this dissertation, skeletal muscle blood flow was measured via the microsphere technique at rest and during exercise (Aim 1), with an acute dose of dietary nitrate via beetroot juice (BRJ) gavage used to determine if supplementation could improve muscle blood flow and alter energetics (Aim 2). VO2max, voluntary running and grip strength tests were used to determine the effect of disease on performance, and to test for an ergogenic effect of BRJ vs. placebo (PL) in healthy and PH rats (Aim 3). Methods: A prospective, randomized, counterbalanced, placebo-controlled trial was used to examine the aforementioned aims across four groups; PH rats (induced with monocrotaline, MCT, 60mg/kg, s.q., 4 weeks) supplemented with BRJ (MCT BRJ, n=9); PH rats supplemented with placebo (MCT PL, n=9); healthy control rats (vehicle, s.q.) supplemented with BRJ (CON BRJ, n=8); healthy control rats supplemented with placebo (CON PL, n=9). Results: Monocrotaline induced a severe PH phenotype evidenced by increased RV wall thickness, RV hypertrophy, RVSP and reduced cardiac output and stroke volume compared to controls (p=<0.001). MCT rats demonstrated lower muscle blood flow at rest, and more prominently during exercise compared to controls (p=0.007-0.047), regardless of supplementation. MCT rats displayed a greater reliance on anaerobic metabolism, demonstrated by increased blood lactate accumulation (p=<0.001), and this was significantly related to reduced blood flow during exercise (r=-0.5879, p=0.001). BRJ supplementation resulted in increased plasma nitrate and nitrite compared to PL (p=<0.001), but at the skeletal muscle level, only nitrate was increased after BRJ. BRJ did not have a significant effect on blood flow, with no improvement during exercise shown vs. PL. Similarly, BRJ did not significantly improve exercise function in MCT or CON rats. Conclusion: MCT rats demonstrated a reduction in muscle blood flow, with BRJ supplementation not resulting in improved flow or exercise performance.

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Mathur, Sunita. "Skeletal muscle dysfunction in people with COPD and recipients of lung transplants." Thesis, 2006. http://hdl.handle.net/2429/18268.

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Chronic obstructive pulmonary disease (COPD) is a respiratory condition with multisystemic effects resulting in skeletal muscle dysfunction. Lung transplantation is a treatment option for people with COPD resulting in improved lung function, however, skeletal muscle dysfunction persists and may be worsened following transplantation due to a period of bedrest and the myopathic effects of immunosuppressant medications. We hypothesized that impairments in skeletal muscle function of the quadriceps and hamstrings in people with COPD would be related to changes in skeletal muscle structure and these impairments would be accentuated in lung transplant recipients. Two pilot studies (Studies 1 and 2) were performed to establish methodology. In Study 3, magnetic resonance imaging showed uniform atrophy of the thigh muscles and intramuscular fat infiltration in the quadriceps and hamstrings of people with COPD compared to age-, sex-, and body mass index (BMI)-matched controls. Notably, eccentric torque normalized to muscle volume was greater in people with COPD compared to controls. Study 4 showed that despite shorter times to task failure for sustained isometric quadriceps contractions, people with COPD showed similar changes in EMG median frequency and amplitude compared to controls. Quantification of cellular features of the vastus lateralis (VL) in Study 5 showed a greater proportion of abnormal muscle and small, angular fibers [i.e. angular fibres] in people with COPD compared to controls. A larger proportion of people with COPD showed increased connective tissue in the VL compared to controls. Comparison of people with COPD to lung transplant recipients in Study 6 showed a similar amount of muscle atrophy, a wide variation in intramuscular fat infiltration, shorter times to task failure for the quadriceps and small, abnormal histological features of the VL. In summary, these findings suggest that although people with COPD demonstrate impairments in skeletal muscle structure and function (e.g. atrophy, fat infiltration, reduced endurance), they have a preservation of eccentric torque and motor unit firing properties. The variation of findings in transplant recipients, partly attributable to a small and diverse sample, limited our ability to test our hypothesis of whether changes in skeletal muscle structure and function would be accentuated in this group of individuals.
Education, Faculty of
Kinesiology, School of
Graduate

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Brown, James B. "Peripheral neuropathy and skeletal muscle dysfunction associated with chronic obstructive pulmonary disease." 2003. http://www.oregonpdf.org.

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"Angiotensin II upregulates PP2Calpha and inhibits AMPK signaling and energy balance leading to skeletal muscle wasting." Tulane University, 2011.

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Abstract:

Congestive heart failure (CHF) and chronic kidney disease (CKD) are characterized by chronic elevated levels of angiotensin II (Ang II) and muscle wasting. Ang II causes skeletal muscle wasting by reducing food intake and by enhancing catabolism. The serine/threonine kinase 5'-Adenosine Monophosphate Activated Protein Kinase (AMPK) functions mainly as a sensor of cellular energy status. It is energy sparing and favors ATP generation. We hypothesized that Ang II induces muscle wasting in part by inhibiting AMPK signaling and altering cellular energy balance. Our results show that Ang II infusion in mice reduced gastrocnemius and quadriceps muscle weight by 26% and 23% respectively, while tibialis anterior and soleus muscles were partially resistant to Ang II wasting, exhibiting 9% and 12% reductions in weight respectively. ATP was depleted in skeletal muscle by 45-74%. Further, Ang II upregulated expression of the protein phosphatase PP2Calpha by 2.6 fold and inhibited AMPK phosphorylation and signaling in wasting gastrocnemius muscle. Importantly, the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) restored AMPK activity to levels of pair-fed controls and abrogated Ang II-induced ATP depletion and muscle wasting. Moreover, AICAR activated Akt and inhibited Ang II-induced increases in E3 ubiquitin ligase expression. These results demonstrate critical roles for energy depletion and AMPK inhibition in Ang II-induced skeletal muscle wasting, and suggest a therapeutic potential for AMPK activators in muscle wasting conditions
acase@tulane.edu

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Dissertations / Theses on the topic 'Skeletal muscle dysfunction and wasting'

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