Lysosomal storage diseases (LSDs) are metabolic diseases which occur as a result of a deficiency of one of the essential lysosomal enzymes, called glycohydrolases. A mutation in the gene encoding one of these enzymes leads to an accumulation of unwanted substrates, resulting in a variety of clinical manifestations. A common symptom found in LSDs is skeletal muscle dysfunction, which includes muscle weakness, atrophy and loss of muscle mass. The genes for lysosomal hydrolases are well characterized; however, much less is known about how mutations in these genes affect the cell and lead to the muscle dysfunction observed. One pathway of interest is autophagy; it has been shown to be essential for maintenance of skeletal muscles. This study sought to investigate the impact of LSDs on autophagy and how this may potentiate muscle dysfunction. We utilized in-vivo and in-vitro models of Sialidosis, Sandhoff Disease, and GM1-Gangliosidosis in order to assess autophagy and its impact on myogenic differentiation in skeletal muscles. Our results demonstrated that autophagy is induced upstream (ULK1 phosphorylation) but is inhibited at the autophagosome to lysosome fusion (p62 upregulation) in LSDs. We also found that myoblast fusion and myogenic differentiation are impaired. We conclude that blocking autophagy impairs myogenic differentiation, which potentiates the muscle dysfunction observed in LSDs. This work highlights autophagy as a new pathway of interest and possible therapeutic target to alleviate muscle dysfunction in LSDs, and other similar neurodegenerative diseases. / Thesis / Master of Science (MSc) / Lysosomal storage diseases (LSDs) occur because of a deficiency of lysosomal glycohydrolases. A common symptom found in LSDs is skeletal muscle dysfunction. Little is known about how a deficiency of these enzymes leads to the clinical manifestations observed. However, one pathway of interest is autophagy. This study sought to investigate the impact of LSDs on autophagy and how this may potentiate muscle dysfunction. We utilized in-vivo and in-vitro models of LSDs to assess autophagy and its impact on myogenic differentiation in skeletal muscles. We demonstrated that autophagy is induced and blocked, and that myoblast fusion and myogenic differentiation is impaired. We concluded that the induction and block of autophagy impairs myogenic differentiation, which potentiates muscle dysfunction.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24172 |
| Date | 23 November 2018 |
| Creators | Padilla, Ron |
| Contributors | Igdoura, Suleiman, Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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