The Role of CCAAT/Enhancer Binding Protein Beta (C/EBPβ) in Skeletal Muscle Satellite Cells after Injury and in Cancer Cachexia

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dc.contributor.authorMarchildon, François
dc.date.accessioned2015-11-27T20:38:31Z
dc.date.available2016-11-30T09:00:07Z
dc.date.created2015
dc.date.issued2015
dc.identifier.urihttp://hdl.handle.net/10393/33373
dc.identifier.urihttp://dx.doi.org/10.20381/ruor-6533
dc.description.abstractCCAAT/Enhancer Binding Proteins are a family of six bZIP transcription factors. C/EBPβ, the second member cloned, has been implicated in adipogenesis and osteogenesis, but the role of C/EBPβ in myogenesis remained undetermined. In adults, muscle-resident stem cells, called satellite cells (SCs), have the greatest propensity to regenerate the skeletal muscle. We found that C/EBPβ is expressed in SCs, and its expression progressively declines upon differentiation. Forcing the expression of C/EBPβ in myoblasts enhanced the expression of the SC marker Pax7, and repressed MyoD and the myogenic genes expression, resulting in the inhibition of myogenesis. Using a SC-specific conditional knockout (cKO) mouse model, we found that cKO myoblasts have decreased expression of Pax7, and we identified Pax7 as a direct target of C/EBPβ action. In vivo, excision of C/EBPβ resulted in muscle hypertrophy at the juvenile age, and adult cKO animals had enhanced muscle regeneration following BaCl2 muscle injury. Moreover, the number of Pax7+ cells in cKO animals decreased following BaCl2 injury. Upon performing a second injury into cKO animals, we demonstrate a decreased muscle fiber size and an exacerbation of the percentage number of SCs. While cKO animals repaired well a BaCl2 injury, regeneration failed in cKO animals following cardiotoxin (CTX) injury. We demonstrate that IL-1β expression is enhanced in muscle after CTX injury when compared to BaCl2, and we found that IL-1β can stimulate the expression of C/EBPβ in myoblasts. Ectopic C/EBPβ expression can protect myoblasts from apoptosis when triggered with thapsigargin, whereas cKO myoblasts are more sensitive to apoptosis. Using cancer cachexia as a model of chronic inflammation, we found that the expression of C/EBPβ is stimulated in the SCs of cachectic animals, and this correlated with a decrease in regenerative capacity. The severity of muscle wasting was not improved in cKO animals, but rather cKO SCs were lost to apoptosis. Together, this study establishes a protective role for C/EBPβ in muscle SCs in conditions of inflammation.
dc.language.isoen
dc.publisherUniversité d'Ottawa / University of Ottawa
dc.subjectC/EBPbeta
dc.subjectSatellite Cell
dc.subjectPax7
dc.subjectMyogenesis
dc.subjectApoptosis
dc.subjectCancer Cachexia
dc.titleThe Role of CCAAT/Enhancer Binding Protein Beta (C/EBPβ) in Skeletal Muscle Satellite Cells after Injury and in Cancer Cachexia
dc.typeThesis
dc.contributor.supervisorWiper-Bergeron, Nadine
dc.embargo.terms2016-11-30 00:00:00
thesis.degree.namePhD
thesis.degree.levelDoctoral
thesis.degree.disciplineMédecine / Medicine
uottawa.departmentMédecine cellulaire et moléculaire / Cellular and Molecular Medicine
CollectionThèses, 2011 - // Theses, 2011 -

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