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Membrane Repair Deficit in Facioscapulohumeral Muscular Dystrophy.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Aug 04; Vol. 21 (15). Date of Electronic Publication: 2020 Aug 04. - Publication Year :
- 2020
-
Abstract
- Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD ( FLExDUX4 ) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4 -targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies.
- Subjects :
- Adult
Aged
Animals
Antioxidants metabolism
Cell Membrane genetics
Cell Membrane metabolism
Cells, Cultured
Female
Gene Expression Regulation drug effects
Homeodomain Proteins antagonists & inhibitors
Humans
Male
Mice
Middle Aged
Muscle Fibers, Skeletal pathology
Muscular Dystrophy, Facioscapulohumeral metabolism
Muscular Dystrophy, Facioscapulohumeral pathology
Muscular Dystrophy, Facioscapulohumeral therapy
Myoblasts metabolism
Myofibrils genetics
Myofibrils metabolism
Oligonucleotides, Antisense genetics
Oligonucleotides, Antisense pharmacology
Oxidative Stress drug effects
Homeodomain Proteins genetics
Muscle Fibers, Skeletal metabolism
Muscular Dystrophy, Facioscapulohumeral genetics
Oxidative Stress genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32759720
- Full Text :
- https://doi.org/10.3390/ijms21155575