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DMD PDF
DMD PDF
1
Clinical features
- Limb-Girdle (LGMD)
- similar to DMD and BMD, involves primarily shoulder and pelvic
girdle muscles
once the growth factors are removed, the myoblasts rapidly stop
dividing, differentiate, and eventually fuse to form fibers
2
Fusion of myoblasts in cell culture
cells fuse and contain multiple nuclei
3
How do muscles handle the stress applied to them?
Dystroglycan-glycoprotein complex
4
Dystrophin
Sarcoglycans
5
Dystrobrevin and syntrophins
Dysbindin
- binds to dystrobrevin and is associated with the DGC
in muscle
6
Dystroglycan
- central protein in the DGC; provides the link between the
cytoskeleton and the basal lamina (ECM)
beta-dystroglycan:
> transmembrane protein
> binds to dystrophin
7
How is muscle damaged when DGC components are missing?
no universal agreement on which mechanism is predominant
- calcium hypothesis: influx of calcium into cytosol overwhelms muscle cells ability
to maintain physiologic Ca++ levels which causes programmed cell death via
activation of proteases such as calpains
(overexpression of calpastatin, an endogenous inhibitor of calpains, has been
demonstrated to reduce necrosis in mdx mice)
- in DMD muscle, nNOS becomes delocalized into the cytosol, reducing its stability;
during exercise, the need for oxygen is increased but loss of NO, a vasodilator, can
lead to muscle ischemia (local anemia due to vasoconstriction)
- nNOS knockout mice do not have muscle disease so nNOS may play a direct role
8
Muscle pathology of muscular dystrophy
- mdx muscle does not exhibit any fibrosis, indicating that collagen regulation at post-
transcriptional stages medaites the extensive fibrosis in human DMD patients
9
Do Duchenne MD boys have central nervous system impairment
as well as skeletal muscle weakness?
promising:
nearly all types of muscular dystrophy arise from single-gene mutations
(one target)
challenging:
efficient delivery of the new gene to most of the striated muscle in the
body (>40% of body mass)
10
expression of smaller forms of the dystrophin gene or dystrophin
mini-genes or the related protein utrophin may be useful alternatives
for gene replacement
- idea came from observation that some mildly affected BMD patients
have deletion mutations that remove large portions of the gene
11
Methods of dystrophin gene repair
exon skipping
- viral vectors are still best choice despite problems with antigenicity
interesting approach: modify viral coat proteins to alter their natural tropism or
selectivity for certain tissues (i.e. so it would bind to muscle tissue rather than liver)
12