Download DMD Reviews 99 - Action Duchenne

Research Review No. 99.
A new role for Dystrophin is discovered in muscle cells.
The Studies:
The authors (1) of these studies from Canada, Germany and Switzerland
examined the exact roles that Dystrophin plays in the muscle cell. In their
introduction they note that Dystrophin, connects the inner skeleton (cytoskeleton)
to the outer part of the muscle cell through the Dystrophin-associated
glycoprotein complex (DGC). Therefore in the absence of Dystrophin, the muscle
fibers are extremely susceptible to injury. The consequence of this is that a
series of multiple cycles of degeneration and regeneration are produced which,
result in elevated inflammation, fibrosis and eventual progressive loss of muscle
mass and function.
In these studies they found that Dystrophin is also highly expressed in
activated muscle stem cells (also known as satellite cells). In these cells it is
associated with the enzyme serine-threonine kinase Mark2. This is also known
as Par1b. Dystrophin thus associates with an important regulator of cell polarity.
They note that in the absence of Dystrophin, expression of Mark2 protein is
reduced (downregulated). The result of this is the inability to localize the cell
polarity regulator, Pard3 to the opposite side of the cell. This therefore
significantly reduces the number of asymmetric divisions in Dystrophin-deficient
satellite cells. These show a loss of polarity including abnormal division patterns.
The way the cell divides is affected is demonstrated by an impaired mitotic
spindle orientation (the way the chromosomes are aligned during cell division)
and prolonged cell divisions. To summarise, the authors note, that “these intrinsic
defects strongly reduce the generation of myogenic progenitors that are needed
for proper muscle regeneration.” They conclude “that Dystrophin has an essential
role in the regulation of satellite cell polarity and asymmetric division.” Their
findings suggest that the muscle wasting, which is such a characteristic of
Duchenne Muscular Dystrophy (DMD), is not just caused “by myofiber fragility,
but also is exacerbated by impaired regeneration owing to intrinsic satellite cell
dysfunction.”
In the same issue of the journal in which the above study is published, is a
revue of this study, which puts it further into the context of DMD (2). The authors
of this review from U.S.A. conclude that, the above study has important
implications for DMD therapeutic interventions. They note that there are a
number of clinical trials are currently in progress dealing with testing direct
replacement of the Dystrophin gene via viral vectors. They note that these
therapies are almost exclusively dealing with the logistics of replacing the
Dystrophin gene. If these ‘mini-dystrophin’ genes do not contain the spectrin
repeats 8 and 9,12 which are required for Mark2 binding , then “they are unlikely
to rescue satellite cell dysfunction in DMD. In future, they urge researchers into
gene therapy to “include these regions in order to rescue Dystrophin function in
both muscle fibers and satellite cells.”
References:
1. Dumont, N.A., Wang, Y.X., von Maltzahn, J., Pasut, A., Bentzinger, C.F.,
Brun, C.E. & Rudnicki, M.A. (2015) Dystrophin expression in muscle stem
cells regulates their polarity and asymmetric division. Nature Medicine.
21(12):1455-1463+.
2. Keefe, A.C. & Kardon, G. (2015) A new role for dystrophin in muscle stem
cells. Nature Medicine. 21(12):1391-1393.
Karl A. Bettelheim
10.1.2016