Craniofacial Muscles

84 F. Pedrosa Domellöf
shown that (1) metabolic changes in the muscle fi ber are capable of initiating
dismantling of the NMJ (Dupuis et al. 2009, 2011 ) and (2) skeletal muscle-restricted
expression of human SOD1 causes motor neuron degeneration and an ALS-like
syndrome in transgenic animal models (Wong and Martin 2010 ) . In other words, the
view on ALS is changing focus from the motor neurons and their supporting cells
centrally to the muscle and the NMJ. The human EOMs differ signi fi cantly from the
other muscles in the body with respect to their metabolic pro fi le and pathways,
structural components, developmental, and regeneration markers, by a total of 338
genes (Fischer et al. 2005 ) ; therefore, some of their intrinsic properties may make
them more resistant to the underlying process behind ALS. Most strikingly, the
EOMs are capable of maintaining a normal laminin composition in their NMJs, in
contrast to the limb muscles from matched ALS patients (Liu et al. 2011 ) . The latter
is particularly important because the ECM may regulate the availability of different
growth and trophic factors, and maintained specialization of the basement membrane
is crucial for proper synaptic function. We propose therefore that the EOMs
are a useful model to study ALS as they may provide insights on strategic adaptation
for longer motor neuron survival or for better preservation of muscle function
which may be important for the development of new therapies for ALS.
5.8 Duchenne and Related Muscle Dystrophies
The selective sparing in muscular dystrophies caused by defects in the dystrophin/dystroglycan
complex (DGC) is by far the most intriguing property of the
EOMs given that these are devastating diseases of childhood that lead to severe
handicap and early death. An understanding of the molecular basis for the selective
sparing of the EOMs in these muscle dystrophies holds the promise of therapeutic
advances for this group of diseases. This has been an active research area,
although the identi fi cation of speci fi c structural adaptations of the EOMs has
remained rather elusive (reviewed by Andrade et al. 2000 ) .
A number of genetic defects affecting almost any of the proteins involved in the
molecular link formed by the ECM on the surface of muscle fi bers, across the cell
membrane, and the subsarcolemmal cytoskeleton are known to cause muscle dystrophies
(Emery 2002 ) , Duchenne muscular dystrophy (DMD) being the most wellknown
of all. In Duchenne and Becker muscular dystrophy, the genetic defect
affects dystrophin (Hoffman et al. 1987 ; Koenig et al. 1988 ) , a cytoskeletal molecule
found in a subsarcolemmal location and a key element of the so-called DGC. The
DGC spans the cell membrane and comprises, among others, dystroglycans, sarcoglycans,
syntrophins, and dystrobrevins, and it connects to actin on the cytoskeletal
side and to laminin 211 (merosin) on the ECM side. The DGC has a fundamental
function providing the mechanical stabilization of the sarcolemma needed for muscle
fi ber integrity and force transmission, and it is also important for cell signaling
(reviewed by Ervasti and Sonnemann 2008 ) . Examples of muscle dystrophies