Biology Reference
In-Depth Information
lacking sarcolemmal nNOS
m
would be subjected to repeated rounds of ischemia
(functional ischemia) causing myofiber damage in dystrophin-deficient muscles
and contributing to the profound exercise intolerance observed in DMD patients.
The loss of nNOS
m
targeting provides a mechanism for the vascular dysfunction
observed in dystrophin-deficient muscle.
Direct evidence that reduced blood flow in postcontraction muscles played a
primary role in the disease pathogenesis came from in vivo microscopy studies.
Pretreatment of dystrophic
mdx
sternomastoid muscle with the NO donor
SNAP (S-nitroso-
N
-acetylpenicillamine), or the cGMP analog 8-CPT-cGMP
(8-chlorophenylthio-cGMP) reversed the ischemic effects of primary arteriole
constriction and prevented contraction-induced myofiber damage (Asai et al.
2007
). This study provided proof of principle that pharmacological augmenta-
tion of NO-cGMP signaling to increase blood supply to active muscles can
reduce postexercise muscle damage. The key role of sarcolemmal nNOS
m
in
preventing ischemic damage in dystrophic muscle was later confirmed by a
study of the therapeutic capability of a
D
H2-R15 minidystrophin cDNA that
could restore sarcolemmal nNOS
m
expression in
mdx
mice (Lai et al.
2009
).
Sarcolemmal nNOS
m
expression restored the ability of
mdx
muscle to oppose
exercise-induced sympathetic vasoconstriction, prevented contraction-induced
fiber degeneration and macrophage infiltration and improved exercise perfor-
mance(Laietal.
2009
). Thus, contraction-induced sarcolemmal nNOS
m
-
derived NO signaling to the VSMC of adjacent resistance vessels plays an
important role in preserving skeletal muscle integrity.
While the importance of contraction-triggered paracrine signaling from skel-
etal muscle nNOS
m
-synthesized NO to the adjacent vasculature is apparent,
dystrophin-associated nNOS in VSMC of blood vessels may also facilitate
opposition to sympathetic vasoconstriction during exercise (Fig.
1
). In
mdx
mice, the loss of dystrophin leads to the reduction of nNOS
m
isoenzyme expres-
sion in both skeletal and vascular smooth muscle (Ito et al.
2006
). It is not clear
whether the nNOS isozyme in question is nNOS
m
or nNOS
a
since both may be
expressed in VSMCs (Boulanger et al.
1998
;Wardetal.
2005
). Nevertheless,
increased smooth muscle specific-expression of dystrophin in
mdx
mice restored
nNOS protein expression and provided an intermediate level of inhibition of
vasoconstriction during contraction (Ito et al.
2006
). Smooth muscle-specific
dystrophin expression in
mdx
mice reduced serum CK levels, indicating
decreased myofiber permeability (Ito et al.
2006
). Unlike the paracrine action
of sarcolemmal nNOS
m
-derived NO on adjacent blood vessels, VSMC nNOS-
derived NO acts in an autocrine fashion to promote smooth muscle cGMP-
dependent relaxation and vasodilation. Together, these data suggest that aberrant
nNOS signaling in VSMCs can also contribute to the microvascular dysfunction
and dystrophic pathology by increasing myofiber permeability and susceptibility to
ischemic damage during exercise. Thus, the vascular dysfunction in
mdx
mice
likely results from simultaneous disruption of nNOS isozyme expression and
signaling in both skeletal and smooth muscle.
