The present review deals with the anatomical
distribution, physiological importance, and pathological
implications of the neuronal-type nitric oxide synthase
(nNOS) in skeletal muscle. Throughout the body, nNOS
is located beneath the sarcolemma of skeletal muscle
fibers. In rodents, nNOS is enriched in type IIb muscle
fibers, but is more homogenously distributed among type
I1 and type I fibers in humans and subhuman primates. It
is accumulated on the postsynaptic membrane at the
neuromuscular junction. An increased concentration of
nNOS is noted at the sarcolemma of muscle spindle
fibers, in particular nuclear bag fibers, which belong to
type I fibers. The association of nNOS with the
sarcolemma is mediated by the dystrophin-g1 ycoprotein
complex. Specifically, nNOS is linked to al-syntrophin
through PDZ domain interactions. Possibly, it also
directly binds to dystrophin. The activity and expression
of nNOS are regulated by both myogenic and neurogenic
factors. Besides acetylcholine, glutamate has also been
shown to stimulate nNOS, probably acting through Nmethyl-
D-aspartate receptors, which are colocalized with
nNOS at the junctional sarcolemma. Functional studies
have implicated nitric oxide as a modulator of skeletal
muscle contractility, mitochondrial respiration, carbohydrate
metabolism, and neuromuscular transmission. A
clinically relevant aspect of nNOS is its absence from
the skeletal muscle sarcolemma of patients with
Duchenne muscular dystrophy (DMD). A concept is presented which suggests that, as a consequence of the
disruption of the dystrophin-glyoprotein complex in
DMD, nNOS fails to become attached to the sarcolemma
and is subject to downregulation in the cytosol