Influence of the MuSK-system on muscle pathology in the mdx mouse model of Duchenne Muscular Dystrophy
Year: 2020
Type: dissertation
Abstract: Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disorder caused by a mutation in the dystrophin gene. The dystrophin-deficient mdx mouse is the most common animal model of DMD. Muscle fibres lacking dystrophin go through cycles of degeneration followed by progressively impaired regeneration. Eventually, degeneration dominates, and fibres are replaced with extracellular matrix (fibrosis). The receptor tyrosine kinase muscle specific kinase (MuSK) has a well-established role in the maintenance of the neuromuscular junction. However, recent work in the lab suggests that it can also reduce the fragility of muscle fibres in the mdx mouse. In this thesis, the tibialis anterior (TA) muscles of 3-4-week-old mdx mice were injected with AAV-MuSK and culled at 12 weeks of age for histological analysis (chapter 3). Supplementation with MuSK-GFP did not alter the composition of the muscle, with no differences in fibre type populations or in the proportion of the muscle occupied by extracellular matrix (collagen I) vs muscle fibre area (myosin). Additionally, in chapter 4 mdx TA muscles were supplemented with other members of the MuSK-system (Dok7 and Rapsyn). This batch of mdx mice were injected at 4 weeks of age with one of the following AAVs encoding: MuSK, mutant MuSK lacking the Ig3 domain (MuSK-ΔIg3), Dok7 or Rapsyn before being culled at 9 weeks of age for histological analysis. Supplementation with AAV-Dok7 was found to improve muscle pathology by reducing the number of recently degenerated/regenerated muscle fibres. Moreover, AAV-MuSK and AAV-Rapsyn were found to reduce muscle fibre girth. Together, these findings suggest a novel role for MuSK-system in protecting dystrophic muscles from damage. Thus, supplementation of MuSK-system components (MuSK, Dok7 and Rapsyn) may present a therapy for DMD and other neuromuscular disorders.
Author: Besa Beqaj
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3042051818