Muscular dystrophy campaign
61 southwark street
London SE10HL
3rd august 2012
In muscle cells, dystrophin
forms part of a group of proteins which acts as a scaffold to link the inside
and outside of the cell. When dystrophin is not in the group (for instance in
Duchene muscular dystrophy) the cell degrades the rest of proteins. Now,
scientists have shows in mouse model that blocking this degradation can
increase levels of the other proteins and help to stabilize the scaffold leading
to reduced muscle damage.
What did the research show?
The dystrophin glycoprotein complex (DGC) is a group of several protein, including dystrophin, which works
to stabilize muscle structure. The complex acts as a scaffold, linking the
internal skeleton of the muscle to structures outside the cell.
In healthy muscle cells,
the dystrophin protein hides a "signal" that tells the cell to
degrade the DGC. The lack of dystrophin in Duchene muscular dystrophy can
uncover this "signal" and lead to the loss of the DGC resulting in a
weaker structural scaffold inside the muscle cell. This means the muscle is
more likely to be damaged when it contracts and eventually leads to the muscle
weakness and wasting seen in Duchene muscular dystrophy.
A team of researchers led by Prof Steve Winder at the University
of Sheffield has tested whether blocking the "signal" for degradation
could prevent the DGC being degraded in the absence of dystrophin. They created
modified mdx mice (an animal model of Duchenne muscular dystrophy) that were missing the signal
and found that this prevented the loss of the DGC. They found that preventing
the loss of the DGC led to an improvement in the muscle structure, and a
reduction in muscle damage.
When the researchers
examined the proteins that were present in the DGC of the modified mdx mice,
they found that a protein called plectin was doing the job that dystrophin
would normally do. Plectin is protein that plays a similar role to dystrophin,
acting as a piece of scaffold to give cells stability and structure. The
researchers do not know why plectin, rather than one of the other scaffold
proteins in the cell, was taking the place of dystrophin in the DGC and this
will need further investigation.
What does this mean for patients?
This research has
increased our understanding of how a lack of dystrophin, leads to muscle
damage. The researchers demonstrated that when dystrophin is missing, a
"signal" is uncovered which tells the cell to degrade the rest of the
DGC. The lack of a DGC means that the muscle has less protection from damage
caused by the muscle contracting. If the "signal" is blocked, or
switched off, then the DGC is not degraded by the cell and plectin can
partially compensate for the lack of dystrophin, reducing muscle damage. This
"signal" represents a new target for potential drugs for Duchenne
muscular dystrophy and, like potential drugs which aim to increase utrophin
production, chemicals that target this pathway may have the potential to treat
all people with Duchene muscular dystrophy, regardless of their mutation.
Although this work is
promising, it is still at a very early stage and has been carried out in an
animal model. The techniques used to block the "signal" in mice could
not be used in a clinical setting and so further research will be needed to
identify candidate drugs which could specifically block the "signal"
to degrade the DGC in the muscles of people with Duchene muscular dystrophy.
