Biology Reference
In-Depth Information
important role for nNOS
m
in the regulation of cardiomyocyte contractility and Ca
2+
flux, functions that are protective in a pathophysiologically distressed heart.
4 Skeletal Muscle Pathogenesis in Duchenne
Muscular Dystrophy
Skeletal muscle nNOS
m
expression, localization, and signaling are severely dis-
rupted in DMD, an X-linked muscle wasting disease that occurs in 1 in every
3,600-6,000 live male births (Davies and Nowak
2006
; Bushby et al.
2009
). DMD
patients exhibit elevated serum creatine kinase activity levels (due to increased
sarcolemmal permeability) and progressive muscle wasting and weakness leading
to loss of ambulation by 12 years of age (Davies and Nowak
2006
). Voluntary limb
and trunk muscles are initially affected, followed by respiratory and cardiac muscle
involvement. DMD results predominantly from frame shift mutations in the gene
encoding dystrophin (Hoffman et al.
1987
).
Dystrophin is a 427 kDa rod-shaped actin-binding protein that resides at the
cytoplasmic face of the sarcolemma (Hoffman et al.
1987
; Koenig et al.
1988
). It
is the namesake of the DGC (dystrophin glycoprotein complex), a multiprotein
complex that links the extracellular basal lamina with the intracellular
g
-actin
microfilament system (Ervasti and Campbell
1993
). Dystrophin stabilizes myofi-
bers against mechanical forces generated during muscle contraction (Ervasti
2007
).
The DGC appears to have a mechanotransduction role whereby dystrophin is
necessary for inhibition of stretch-activated Ca
2+
channel activity (Vandebrouck
et al.
2001
). As mentioned above, dystrophin also serves as a scaffold on which
signaling molecules are localized primarily by the adaptor protein
a
-syntrophin
(Percival et al.
2006
). nNOS
m
is the best characterized ligand of
a
-syntrophin
(Brenman et al.
1996
; Kameya et al.
1999
; Adams et al.
2000
). The mode of
nNOS
m
binding to
a
-syntrophin leaves the PDZ domain of nNOS
m
free to bind
other proteins including phosphofructokinase (Brenman et al.
1996
; Hillier et al.
1999
; Firestein and Bredt
1999
; Adams et al.
2001
). Dystrophin deficiency leads to
the loss of
a
-syntrophin and nNOS
m
from the DGC. Mislocalized nNOS
m
fails to
override exercise-induced sympathetic vasoconstriction (Thomas et al.
2003
).
Thus, the loss of dystrophin simultaneously impacts muscle structural integrity
and uncouples contraction-induced signaling, including NO-mediated signal trans-
duction.
Disruption of nNOS
m
expression and signaling occurs not only in DMD, but also
in other myopathies, including: Becker Muscular Dystrophy (also from less patho-
genic mutations of dystrophin), Limb Girdle Muscular Dystrophies 2C, 2D, and 2E
(resulting from mutations of
g
-,
a
-, and
b
-sarcoglycan, respectively), and Ulrich
Congenital Muscular Dystrophy (collagen VI mutation) (Brenman et al.
1995
;
Chang et al.
1996
; Chao et al.
1996
; Crosbie et al.
2002
; Kobayashi et al.
2008
).
These myopathies are all characterized by the absence of sarcolemmal nNOS
m
protein expression, whereas both cytosolic and sarcolemmal nNOS
m
expression are
