Since its identification in 1997 as the common receptor for Coxsackie and adenovirus (CAR) multiple lines of evidence argue in favor of CAR contributing to aspects of cell adhesion in addition to serving as a viral receptor. Nevertheless, a precise biological role for CAR remains to be identified suggesting the receptor may participate in a variety of cellular functions that reflect its tissue specific and developmentally regulated expression. This thesis elucidates aspects of CAR biology in mature striated muscle by providing studies that encompass (i) its physiological cellular/subcellular localization and expression in mature striated muscle (ii) its expression profile in human diseased skeletal muscle and (iii) the potential consequences of its sustained expression in mature striated muscle where its levels would otherwise be highly attenuated. / In non-diseased, mature striated muscle despite low and barely detectable levels of the CAR transcript (cardiac and skeletal muscle respectively), we identified CAR as a novel component of the neuromuscular junction and showed its expression to be isoform-specific in contrast to the intercalated discs, where both predominant CAR isoforms are detected. We then investigated the expression of CAR at the level of human skeletal muscle disease. From these studies we observed that in diseases characterized by active necrosis and regeneration, extrasynaptic CAR expression is detectable in regenerating fibers and co-expressed with other previously described markers of regeneration at a high degree of coincidence. Moreover, extrasynaptic CAR expression appears to be a highly reliable indicator of the regenerative process offering potential use at the diagnostic level. Following these investigations, our final studies involved assessing whether sustained CAR expression might affect the normal homeostasis in skeletal and cardiac muscle using a transgenic mouse model. We discovered that transgenic mice expressing sustained high levels of CAR (as seen in the CAR+/+ transgenics) develop a lethal necrotizing myopathy characterized by dual deficiencies in dystrophin and dysferlin, two proteins pivotal in maintaining plasmalemmal integrity, raising the possibility for a previously unrecognized cause of skeletal muscle dysfunction. / Collectively these findings argue that in non-diseased mature skeletal and cardiac muscle, CAR expression is restricted to the neuromuscular junction and cardiac intercalated discs but in diseases of skeletal muscle characterized by active necrosis and regeneration, extrasynaptic CAR expression is reexpressed at these sites of injury/repair. In addition they raise the possibility that sustained CAR expression in mature skeletal muscle may be associated with altered muscle homeostasis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111881 |
| Date | January 2006 |
| Creators | Shaw, Christian A. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Neuroscience.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002651488, proquestno: AAINR38644, Theses scanned by UMI/ProQuest. |
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