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Theses (Ph. D.)--Marshall University, 2007. / Title from document title page. Includes abstract. Document formatted into pages: contains x, 102 pages including illustrations. Bibliographical references at the end of each chapter.
Saunders, Claire Ann
09 June 2009
The efficacy of sodium phosphate D6 in delaying the onset of muscle fatigue during short duration, high intensity exerciseBeukes, Stéfan 29 July 2009 (has links)
The Regulation of Telomerase Reverse Transcriptase (TERT) by CCAAT/Enhancer Binding Protein β (C/EBPβ) During Skeletal Muscle DifferentiationSlivitzky, Kira January 2017 (has links)
Our lab has identified the bZIP transcription factor CCAAT/Enhancer Binding Protein beta (C/EBPβ) as a negative regulator of myogenic differentiation. C/EBPβ is highly expressed in satellite cells and is downregulated during myogenic differentiation, a step that is critical for terminal differentiation, as ectopic C/EBPβ expression blocks this process. Telomerase has been identified as a C/EBPβ target gene in liver and other systems, and has been implicated in the regulation of muscle regenerative responses in models of Duchenne Muscular Dystrophy. Given that C/EBPβ is overexpressed in models of muscle wasting, and high levels of telomerase inhibit differentiation, I hypothesized that C/EBPβ inhibits myogenic differentiation through upregulation of TERT (telomerase reverse transcriptase) expression. I demonstrate that overexpression of C/EBPβ in myoblasts increases mTERT expression under both growth and differentiation conditions. Conversely, loss of C/EBPβ expression in myoblasts using shRNA technology or after isolation of primary myoblasts from conditional knockout mice, results in a downregulation of TERT expression and activity. When TERT was pharmacologically inhibited or knocked down using a shRNA, there was a significant improvement in differentiation and fusion in C2C12 myoblasts overexpressing C/EBPβ as evidenced by an increase in the number of MHC+ fibers and expression of muscle-specific differentiation genes. Interestingly, I found that C/EBPβ and TERT expression were increased in both embryonic and alveolar models of rhabdomyosarcoma. In response to this, a knockdown of C/EBPβ in rhabdomyosarcoma cells decreased TERT expression and activity, and enhanced differentiation but not fusion in a model of embryonic rhabdomyosarcoma. These findings illustrate the novel regulation of TERT in skeletal muscle by C/EBPβ, and reveal C/EBPβ as an attractive therapeutic target for the treatment of muscle diseases such as rhabdomyosarcoma.
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