Craniofacial Muscles

5 Extraocular Muscle Response to Neuromuscular Diseases…
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caused by defects in genes related to the DGC are some forms of limb-girdle muscular
dystrophy, which are due to defects in the different sarcoglycans (Bonnemann et al.
1995 ; Lim et al. 1995 ) and congenital muscle dystrophies (reviewed by Muntoni and
Voit 2004 ) caused by defects involving the laminin alpha-2 chain, also known as
merosin-de fi cient congenital muscular dystrophy (Helbling-Leclerc et al. 1995 ) ,
alpha-7-integrin (Hayashi et al. 1998 ) , or collagen VI genes.
The EOMs are clinically and histologically spared in DMD and in animal models
of muscle dystrophies due to mutations in dystrophin, the laminin alpha-2 chain,
and sarcoglycans (for references see Andrade et al. 2000 ) . The laminin chain composition
of the human EOMs differs from that of skeletal muscle fi bers. The EOMs
co-express laminin alpha-4, alpha-5, and beta-2 chains, in addition to alpha-2 and
beta-1 chains present in all skeletal muscle fi bers (Kjellgren et al. 2004 ) . The
co-expression of additional laminin chains is most likely a speci fi c mechanism that
protects the human EOMs in merosin-de fi cient congenital muscle dystrophy.
Supporting this hypothesis, the EOMs of the dy3k/dy3k mice, which completely
lack the laminin alpha-2 chain, remain unaffected, and co-express the additional
laminin chains, in contrast to the affected limb muscles (Nystrom et al. 2006 ) .
Possible general factors of importance for the selective sparing of the EOMs in
muscular dystrophy may be the very small diameter of muscle fi bers and the very
small loads that these fi bers work against. Differences in calcium homeostasis may
also be a relevant factor, as the EOMs have a superior capacity to handle calcium
and calcium overload is a part of the pathogenic process in these diseases. However,
an increased regenerative capacity may be the single most relevant property for the
selective sparing of the EOMs in DMD (Kallestad et al. 2011 ) . The gene expression
pro fi les of the EOMs differ from those of limb muscle by increased expression of
genes related to regeneration, growth, and development (Porter et al. 2001 ; Fischer
et al. 2005 ) . Experiments using incorporation of bromodeoxyuridine (brdU) indicate
that the EOMs have signi fi cant activation of muscle precursor cells and addition
of myonuclei to the muscle fi bers, even in the absence of disease (McLoon
et al. 2004, 2007 ) . A recent study identi fi ed a subpopulation of muscle cell precursors
with special properties that are present at higher numbers in the EOMs from
both mdx and mdx/utrophin −/− mouse models of DMD, compared to their limb muscles,
strongly suggesting an important role for successful regeneration in the sparing
of the EOMs (Kallestad et al. 2011 ) .
5.9 Summary
In summary, the EOMs display a complex disease pro fi le when compared with limb
skeletal muscles. Their propensity for, or sparing from, various forms of muscle
pathology are under intensive study in many laboratories. Hopefully, uncovering the
mechanisms for EOM sparing or involvement in speci fi c muscle disease entities
will help direct translational research towards new therapies for treatment.