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(Thomas et al.
1998
; Firestein and Bredt
1999
; McConell and Wadley
2008
;
Suzuki et al.
2007
; Percival et al.
2008
,
2010
; Kobayashi et al.
2008
; Wehling-
Henricks et al.
2009
). Therefore, nNOS
m
appears to control physiological pathways
that collectively regulate metabolic energy flux, particularly during muscle con-
traction. These roles also support the proposition that muscle nNOS
m
function is
most important under conditions of physiological stress, particularly prolonged
inactivity or exercise. In agreement with this proposition, the muscles of trained
athletes express higher levels of nNOS
m
, while nNOS
m
levels are lower in less
active or sedentary muscles and often absent in myopathic muscles; therefore,
establishing a close relationship between nNOS
m
expression and muscle activity
(Brenman et al.
1995
; Chang et al.
1996
; Chao et al.
1996
; Crosbie et al.
2002
;
McConell et al.
2007
; Suzuki et al.
2007
; Kobayashi et al.
2008
).
The exercise performance of muscle is highly dependent on oxygen supply.
Perhaps, the best studied function of nNOS
m
is its ability to attenuate resistance
vessel vasoconstriction, matching oxygen delivery with demand during muscle
contraction (Thomas and Victor
1998
;Thomasetal.
1998
,
2003
). The localiza-
tion of nNOS
m
to the sarcolemma is critical for this vasomodulatory function and
cannot be compensated for by cytoplasmic nNOS
m
or Golgi nNOS
b
(Thomas
et al.
2003
; Percival et al.
2010
). Taken together, these data demonstrate a role for
nNOS
m
in regulating oxygen delivery during muscle contraction and strongly
support a role for nNOS
m
in regulating the exercise performance of skeletal
muscle.
3 nNOS Signaling in Cardiac Muscle
As in skeletal muscle, nNOS
m
-synthesized NO in the heart has emerged as an
important autocrine regulator of cardiomyocyte contractility and coronary blood
flow (Barouch et al.
2002
; Sears et al.
2003
; Zhang et al.
2008
; Seddon et al.
2009
,
Fig.
1
). Cardiac nNOS
m
plays an essential role in promoting relaxation of
the myocardium and may do so via the regulation of Ca
2+
flux. For example,
nNOS
m
-derived NO decreases inward Ca
2+
movement (thereby reducing basal
contractility) by negatively regulating the activity of the L-type Ca
2+
channel
(Sears et al.
2003
). However, in contrast to its distribution in skeletal muscle,
nNOS
m
is primarily localized to the sarcoplasmic reticulum in cardiac myocytes
in a complex with the ryanodine receptor Ca
2+
-release channel (RyR2), suggesting
tissue-specific differences in nNOS
m
function in excitation-contraction coupling
(Xu et al.
1999
; Sears et al.
2003
; Fig.
1
). Cardiac nNOS
m
is thought to serve
a cardioprotective role under conditions of pathophysiological stress. For example,
nNOS
m
translocation to the sarcolemma occurs during myocardial infarction and
heart failure, where it blunts
b
-adrenergic signaling and reduces cardiac contractility
(Bendall et al.
2004
). Additional support for a cardioprotective role comes from
findings that nNOS
m
depletion exacerbates maladaptive cardiac remodeling follow-
ing myocardial infarction (Saraiva et al.
2005
). These data strongly support an
