Biomedical Engineering Reference
In-Depth Information
accounting for approximately 1 % of the X chromosome. Due to its large size
(2.4 Mb), it is particularly prone to deletions and point mutations. Dystrophin
serves as a structural connection between the actin cytoskeleton and the extra-
cellular matrix, allowing for the transmission of external forces into the cell.
Dystrophin deficiency results in loss of membrane integrity, and subsequent
degeneration and necrosis [
9
].
DMD, the most severe dystrophinopathy, is fatal, affecting 1 in 3,500 male
births. At the time of birth, there are no overt signs of pathology, but once the
infant reaches the walking stage, he may be perceived as clumsy. Excessive
degeneration results in kyphosis and scoliosis of the spine, and by early adoles-
cence, approximately 95 % of patients are confined to a wheelchair. By the age of
20, about 90 % die due to respiratory or cardiovascular failure. Whereas there is no
functional dystrophin expressed in DMD patients, with the exception of few
revertant fibers, expression of a truncated function form of dystrophin results in
BMD. Many BMD patients enjoy a normal lifespan, but in some of the more
severe forms, patients may die as young as 40 [
7
].
There are also autosomal muscular dystrophies, such as limb girdle muscular
dystrophy (LGMD). This condition may be caused by mutations in various com-
ponents of the sarcoglycan complex, which again, maintains membrane integrity.
LGMD principally affects proximal muscles of the trunk and limbs, whereby it
derives its name. Although there is a lot of variability, many of the LGMD subtypes
are not severe in phenotype, and may not arise until later in life [
10
].
6.1.2 Current Treatments
At this time, there are no pharmaceutical drugs that can be used to effectively
accelerate muscle healing following injury. Nonsteroidal anti-inflammatory drugs
(NSAIDs) are often prescribed to ease the pain and inflammation associated with
injury. NSAIDs relieve these symptoms temporarily through the inhibition of
cyclooxygenase 1 and 2 (COX-1,2), reducing the synthesis of prostaglandins,
principal participants in inflammation. However, studies show that blocking
inflammation does in fact delay wound healing [
11
]. We have previously also
reported that treatment with NS-398, a specific inhibitor of COX-2, immediately
following injury delays regeneration and increases fibrotic scarring [
12
]. Inflam-
mation plays a critical role not only in the clearance of cellular debris, but also in
SC activation. Thus, blocking inflammation early in wound repair could in turn
delay SC activation, and therefore delay recovery from injury. Indeed, we found
that NS-398 treatment decreased myogenic progenitor cell proliferation and dif-
ferentiation. In agreement with this hypothesis, a study by Mackey and colleagues
found that indomethacin, an often prescribed NSAID, decreases exercise-induced
SC proliferation [
13
]. Therefore, while NSAIDs relieve the pain associated with
injury, they are likely detrimental to the overall regeneration process.
