Biology Reference
In-Depth Information
The relationship between skeletal muscle performance, blood supply, and
nNOS
m
is complex. Kobayashi and coworkers concluded that the absence of
contraction-induced sarcolemmal nNOS
m
signaling to the adjacent VSMC was
responsible for postexercise inactivity. While the beneficial effects of PDE5A
inhibition are clear, the mechanisms by which they occur are not. Although it
remains to be determined whether augmentation of nNOS
m
signaling from skeletal
to VSMC is the sole pathway responsible for these beneficial effects, it seems
unlikely for several reasons. First, augmentation of smooth muscle NO-cGMP
signaling alone in
mdx
mice can enhance blood supply and reduce membrane
permeability (Ito et al.
2006
). Since PDE5A expression is high in VSMC, inhibition
of PDE5A may promote smooth muscle relaxation independently of NO produced
by skeletal muscle. Second, PDE5A inhibition affects vascular bed function
throughout the cardiovascular system and likely enhances systemic hemodynamics
during exercise. Third, additional, recently identified nNOS-sGC-PKG signaling
pathways in skeletal muscle control postexercise muscle strength that could be
affected by PDE5A inhibition in skeletal muscle (Percival et al.
2010
). Fourth,
nNOS knockout mice exhibit pronounced muscle fatigue and weakness during
exercise that could contribute to the observed postexercise weakness (Percival
et al.
2008
). Finally, acute sildenafil treatment enhances cardiac function in
mdx
mice and could assist cardiovascular recovery (Khairallah et al.
2008
).
Thus, the factors that contribute to the postexercise inactivity after mild exercise
in
mdx
mice are many and likely include muscle weakness during and/or after
exercise. The beneficial effects of PDE5A inhibition likely reflect effects at many
sites of action, making mechanistic interpretation of these whole animal studies
very difficult. Nonetheless, while the molecular mechanisms responsible are debat-
able, Kobayashi et al. have clearly shown that PDE5A inhibition in
mdx
mice
provides nNOS-dependent enhancement of activity during and after exercise as
well as reducing exercise-induced muscle damage.
9 Conclusion
Although the examples of therapeutic benefit are few and the mechanisms are
poorly understood, the evidence that PDE5A inhibition reduces skeletal and cardiac
muscle damage, particularly contraction-induced myofiber damage during exercise,
is compelling. PDE5A inhibition also enhances exercise performance, reduces the
negative effects of mild exercise, and enhances the workload capacity of dystrophin-
deficient hearts. Thus, further studies are required to flesh out this promising
therapeutic approach. However, mice are not men and ultimately, any efficacy of
PDE5A inhibitors in preclinical studies must be validated in a clinical setting.
Efficacy in both skeletal muscle and cardiac tissue makes PDE5A inhibition
particularly attractive as a therapeutic approach and warrants further research into
the potential utility of PDE5A inhibition in the treatment of cardiovascular disease
in DMD.
