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http://hdl.handle.net/11375/27043
Title: | SATELLITE CELLS AND MYOTONIC DYSTROPHY TYPE 1 (DM1) |
Other Titles: | CHARARACTERIZATION OF SATELLITE CELLS AND ASSOCIATED MYOGENIC DEFECTS IN DM1 WITH AEROBIC TRAINING |
Authors: | Manta, Katherine |
Advisor: | Tarnopolsky, Mark |
Department: | Medical Sciences (Cell Biology and Metabolism) |
Keywords: | DM1, muscle stem cells, myotonic dystrophy type 1, satellite cells, aerobic training, exercise |
Publication Date: | 2021 |
Abstract: | Myotonic dystrophy type 1 (DM1) is an autosomal dominant and progressive neuromuscular disorder caused by the CTG trinucleotide repeat expansion in the 3’ untranslated region of the DMPK gene. Clinical manifestations include extensive atrophy of skeletal muscle (SkM) concomitant with muscle weakness, that develops in a distal to proximal fashion. Central to muscle plasticity is the satellite cell (SC), a muscle specific stem cell that, upon activation, facilitates muscle repair and regeneration. To date, SCs have yet to be elucidated in DM1; therefore, the aim of the present study was to extensively characterize the PAX7+ SC population, along with other indices of muscle quality in SkM. DM1 patients (6 women, 5 men) performed stationary cycling 3 times per week for 12wks, with biopsies taken from the Vastus lateralis pre- (PRE) and post-endurance exercise intervention (POST). Age-matched, healthy controls (CTRL) were used for comparison of baseline measures. Type 1 and 2 myofiber-specific PAX7+ cells were significantly greater in DM1 patients (PRE), in comparison to CTRL (2.24- and 1.84-fold, respectively), with type 2 SC content further increasing following training (p<0.05). In addition, protein expression of myogenic regulatory factors PAX7 and myogenin were significantly higher in DM1 compared to CTRL, with no training effects observed. Both immunohistochemical and immunoblotting analysis showed that activated MYOD+/PAX7+ cells did not significantly differ in DM1 vs. CTRL. FISH- IF analysis of CUG repeats show that 30% of SCs in DM1 were positive for these inclusions. Muscle capillarization was significantly lower in type 2 fibers in DM1 vs CTRL, which was fully rescued with training (p<0.05). At baseline, DM1 muscle showed the presence of de novo and fat infiltrated fibres, as well as fibrosis, that were relatively non-existent in the CTRL. In vitro results show patient-derived myoblasts exhibit a proliferation defect. Furthermore, myoblasts showed impairments in both glycolysis and mitochondrial respiration, with the latter being completely normalized to CTRL in myotubes. Our novel findings display an increased, albeit non-functional, SC pool in DM1 SkM indicated by disturbances in the myogenic program and overall poor muscle quality. We show that both SCs and SkM remain responsive to exercise training, suggesting therapeutic potential. We also suggest that mitochondrial dysfunction may underpin these impairments in the myogenic program. |
URI: | http://hdl.handle.net/11375/27043 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Manta_Katherine_202109_MSc.pdf | 3.42 MB | Adobe PDF | View/Open |
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