Evaluation of the Therapeutic Utility of Phosphodiesterase 5A Inhibition in the mdx Mouse Model of Duchenne Muscular Dystrophy - Phosphodiesterases as Drug Targets - page 330

substantially reduced ( 80%) in dystrophin-deficient muscles (Chang et al. 1996 ).

Thus, dystrophin is necessary for the normal expression and localization of nNOS m .
The mechanisms by which nNOS m signaling is disrupted remain to be determined
in other myopathies. In summary, it is clear that nNOS signaling abnormalities are
common to a broad spectrum of muscle diseases.
In addition to the dysregulation of nNOS m , many other proteins and pathways
are deregulated in dystrophin-deficient muscle. The loss of dystrophin increases
muscle instability and permeability, reflected by excessive Ca 2+ influx. In turn, Ca 2+
overload leads to activation of proteases and mitochondrial dysfunction causing
muscle necrosis and cycles of muscle cell degeneration and regeneration (Davies
and Nowak 2006 ). Regeneration is easily observed histologically as clusters of
centrally nucleated fibers. Muscle breakdown is accompanied by infiltration of
inflammatory cells, particularly macrophages. Initially, the regenerative capacity
of dystrophin-deficient muscle keeps pace with degeneration, but is soon exhausted
and myofibers are gradually replaced by adipose and fibrous connective tissue
(Davies and Nowak 2006 ).
Corticosteroid treatment, despite significant side effects and limited efficacy, is
the mainstay therapy for the preservation of skeletal muscle function in DMD
(Manzur et al. 2008 ). Death typically ensues in the third decade of life with 75%
of DMD patients dying from respiratory failure while the remainder succumbs to
heart failure (Finsterer and St ollberger 2003 ). However, the incidence and severity

of cardiac dysfunction are on the rise because of improvements in noninvasive
ventilatory support (Eagle et al. 2007 ). Better understanding of the cascade of
pathological changes in dystrophin-deficient muscles is necessary to identify new
targets for therapeutic pharmacological intervention in the short term.
The effects of dystrophin-deficiency have been extensively studied in the mdx
mouse, an animal model for DMD. As is the case in humans, mdx mice exhibit
significant skeletal muscle weakness, susceptibility to fatigue, exercise intoler-
ance, shorter lifespan, elevated serum creatine kinase activity, widespread muscle
degeneration and regeneration, muscle necrosis, Ca 2+ overload, fibrosis, and
inflammation (Stedman et al. 1991 ; Davies and Nowak 2006 ; Chamberlain et al.
2007 ; Willmann et al. 2009 ). Dystrophin-deficient mdx myofibers exhibit a char-
acteristic susceptibility to lengthening contraction that may result from inappro-
priate stretch-activated Ca 2+ channel activity (Petrof et al. 1993 ; Dellorusso et al.
2001 ; Whitehead et al. 2006 ). The diaphragm muscle in mdx mice best recapitu-
lates the pathology observed in the skeletal muscles from DMD patients (Stedman
et al. 1991 ). However, mice are less affected by the absence of dystrophin than
humans and exhibit a slower and milder disease progression. Highly effective
compensatory mechanisms are clearly at play in dystrophin-deficient tissues of
mdx mice. Increased expression of utrophin, a functional paralogue of dystrophin,
is thought to play a significant compensatory role (Davies and Nowak 2006 ).
Overall, however, mdx mice represent a useful model for investigating dystrophic
pathology and for evaluating the efficacy of experimental treatments.

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