Biology Reference
In-Depth Information
Thus, dystrophin-deficiency has serious negative consequences for cardiac as well
as skeletal muscle function.
Unlike skeletal muscle, the role of nNOS in the dystrophic heart has not been
investigated in humans. Also, studies of NO-cGMP signaling in
mdx
mouse hearts
are limited. Knowledge of the NOS-signaling pathway activity in dystrophy is very
important from a therapeutic standpoint, since NO is required for many of the
cardioprotective effects of sildenafil (Nagayama et al.
2008
). In the absence of NO,
sGC may not be sufficiently active and, consequently, fails to produce physiologi-
cally sufficient amounts of cGMP, rendering the inhibition of cGMP-hydrolyzing
PDEs therapeutically ineffective (Fernhoff et al.
2009
).
nNOS activity, but not nNOS protein expression, is inhibited in dystrophin-
deficient cardiac muscle. Cardiac nNOS
m
levels appear unaffected by dystrophin-
deficiency, despite a significant reduction in nNOS
m
activity (Bia et al.
1999
;
Wehling-Henricks et al.
2005
). The activity of endothelial NO synthase (eNOS),
the other NO-generating enzyme in cardiomyocytes, is unaffected by the absence of
dystrophin (Bia et al.
1999
). Elevated expression of atrial natriuretic peptide
(the ligand for the transmembrane guanylyl cyclase ANP receptor A [NPR-A])
mRNA in
mdx
hearts is consistent with deficits in cGMP signaling in dystrophic
cardiac tissue (Khairallah et al.
2007
) and suggests that increased ANP pathway
activity may be a compensatory mechanism in the
mdx
heart.
Although the impact of dystrophin-deficiency on cardiac function has received
less attention than in skeletal muscles, it is clear that
mdx
mice develop a less
severe, but pronounced cardiomyopathy compared with humans. Two important
distinctions between
mdx
and DMD hearts are that ventricular fibrosis is less
extensive and chamber dilation is not pronounced in murine
mdx
hearts (Quinlan
et al.
2004
; Wehling-Henricks et al.
2005
; Spurney et al.
2008
). The reasons for
these differences are unknown. However, as in humans, the absence of dystrophin
initiates a similar cascade of pathological events that leads to increased membrane
permeability and Ca
2+
overload, culminating in cardiomyocyte necrosis and death.
Increased cardiomyocyte death likely results in part from an increased susceptibil-
ity to contraction-induced damage (Danialou et al.
2001
). The predisposition of
dystrophin-deficient cardiomyocytes to necrosis and mechanical stress results in
significant contractile dysfunction.
Early
mdx
mouse studies suggested that cardiomyopathy could only be
detected around 8 months of age (Quinlan et al.
2004
). However, recent studies
have demonstrated cardiac dysfunction including LV systolic and diastolic dys-
function in mice as young as 8-10 weeks of age (Danialou et al.
2001
;Wuetal.
2008
;Khairallahetal.
2007
). Cardiac dysfunction is not evident from noninva-
sive in vivo analysis at these young ages, suggesting compensatory mechanisms
in vivo. These findings are consistent with the progression of DCM in DMD
patients, where early cardiomyopathy goes largely unnoticed, only becoming
clinically symptomatic in the second decade of life. Hearts from 9- to 10-
month-old
mdx
mice exhibit marked systolic dysfunction and pathological LV
remodeling (Quinlan et al.
2004
; Spurney et al.
2008
). Also, myocardial perfor-
mance index (MPI) is significantly increased, indicative of increased cardiac
