Skeletal muscle disease (myopathy) carries an enormous psychological, social and economic impact on the lives of the patients and their caregivers. There is also an appreciable amount of economic burden on the healthcare system and our society especially when most patients are in their childhood/adolescent lives. It is not a surprising fact that a percentage of myopathies are of undetermined cause, which makes the need to identify new genes that play a critical role in muscle health of paramount importance. The Xin gene is designated as an indispensable component for the normal development and morphogenesis of striated muscle; however, the exact roles of Xin in skeletal muscle are still undefined. Studies to date have demonstrated that Xin is expressed in activated satellite cells and newly formed myofibers following tissue injury. When using in vitro reduction of Xin expression in skeletal muscle cells, the outcome was impairments in satellite cell function and muscle response to injury. That said, there is still a significant lack of knowledge in the literature regarding the in vivo effects of the absence of Xin on skeletal muscle structure and function. Therefore, the aim of our studies was to characterize skeletal muscles in the absence of Xin and identify the potential roles of Xin in maintaining muscle integrity and health. In our studies, we uncover a new form of muscle disease resulting from the lack of Xin in a mouse model (Xin-/- mice). Xin-/- skeletal muscles show a mild form of myopathy at the light microscopy level that is associated with ultrastructural and functional defects peculiar to the Ca2+ handling. In addition, Xin-/- muscle demonstrated features of mitochondrial dysfunction that are likely secondary to the Ca2+ defects caused by the absence of Xin. Our studies provide a platform to investigate the potential manifestation of “loss of function” mutation of Xin in skeletal muscle and its possibly related pathology in human diseases. / Thesis / Doctor of Philosophy (PhD) / Skeletal muscle covers the bones, produces movements and stabilizes joints. Diseases of skeletal muscle are common. Specifically, inherited diseases of skeletal muscle can cause an inability to eat, walk, run, work and even breathe. By starting at an early age, these conditions may result in the patient being bed-ridden with severe psychological, social and financial burdens for them and their caregivers. When skeletal muscles that control breathing are involved, death can occur at a young age. A considerable proportion of skeletal muscle disease are of unknown cause, and therefore, there is a constant need to discover more factors that influence muscle health to provide treatment plans for these patients. This dissertation uncovers the role of a new factor, Xin, involved in keeping skeletal muscle healthy. The achieved results of our studies will help physicians use this knowledge into identifying new types of muscle disease and providing targeted treatments for patients.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/21246 |
| Date | January 2017 |
| Creators | Al-Sajee, Dhuha |
| Contributors | Hawke, Thomas, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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