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Cellular Reprogramming in Skeletal Muscle after Repeated Exposures to Endotoxin

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dc.contributor.authorDenko, Laura Michelleen
dc.contributor.committeechairHulver, Matthew W.en
dc.contributor.committeememberDavy, Kevin P.en
dc.contributor.committeememberLi, Liwuen
dc.contributor.committeememberFrisard, Madlyn I.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2017-04-04T19:49:23Zen
dc.date.adate2012-08-09en
dc.date.available2017-04-04T19:49:23Zen
dc.date.issued2012-06-21en
dc.date.rdate2016-09-27en
dc.date.sdate2012-06-29en
dc.description.abstractObesity-related metabolic derangements have been linked to toll-like receptor 4 (TLR4), an innate immune system receptor, due to its role in proinflammatory pathways. Lipopolysaccharide (LPS), a gram-negative bacteria cell wall component, is the ligand for TLR4, and has been shown to be elevated in states of metabolic disease. Heightened levels of circulating endotoxin is termed metabolic endotoxemia and has been linked to systemic inflammation which is associated with obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). Immune cells exhibit a protective ability to develop endotoxin tolerance. The objective of this study was to determine if endotoxin tolerance exists in skeletal muscle cells, and if a condition that mimics a state of over nutrition, such as elevated levels of fatty acids, affect this tolerance. To this end, L6 skeletal muscle cells were treated with low (50 pg/mL)- and high (500 ng/mL)-doses of LPS, with and without the presence of free fatty acids (FFAs). Tolerance was assessed by measuring: 1) changes in mRNA expression of interleukin-6 (IL-6) and monocyte chemoattractant-1 (MCP-1) as markers of a pro-inflammatory response; and 2) mRNA levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1-°) and mitochondrial oxidative capacity via an XF24 Flux Analyzer (Seahorse Bioscience) as measures of the metabolic response. Tolerance to LPS was observed in response to low- and high-doses with MCP-1 mRNA transcription but not IL-6. Changes in PGC1-° and mitochondrial OCR exhibited a tolerant effect in response to the high dose of LPS but not the low dose. The addition of free fatty acids to LPS treatments did not prevent the tolerant effects under any conditions. In conclusion, LPS tolerance exists in skeletal muscle cells but appears to differ depending on pro-inflammatory target and LPS concentration. Additionally, fatty acids, in the current model, have no effect on LPS tolerance.en
dc.description.degreeMaster of Scienceen
dc.identifier.otheretd-06292012-114135en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-06292012-114135/en
dc.identifier.urihttp://hdl.handle.net/10919/76808en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectTLR4en
dc.subjectendotoxinen
dc.subjectLPSen
dc.subjectskeletal muscleen
dc.titleCellular Reprogramming in Skeletal Muscle after Repeated Exposures to Endotoxinen
dc.typeThesisen
dc.type.dcmitypeTexten
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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