The
ubiquitin-
proteasome system is the primary proteolytic pathway implicated in skeletal muscle
atrophy under catabolic conditions. Although several studies showed that
proteasome inhibitors reduced proteolysis under catabolic conditions, few studies have demonstrated the ability of these inhibitors to preserve skeletal muscle mass and architecture in vivo. To explore this, we studied the effect of the
proteasome inhibitor Velcade (also known as
PS-341 and
bortezomib) in denervated skeletal muscle in rats. Rats were given vehicle or
Velcade (3 mg/kg po) daily for 7 days beginning immediately after induction of
muscle atrophy by crushing the sciatic nerve. At the end of the study, the rats were euthanized and the soleus and extensor digitorum longus (EDL) muscles were harvested. In vehicle-treated rats,
denervation caused a 33.5 +/- 2.8% and 16.2 +/- 2.7% decrease in the soleus and EDL muscle wet weights (%
atrophy), respectively, compared to muscles from the contralateral (innervated) limb.
Velcade significantly reduced
denervation-induced
atrophy to 17.1 +/- 3.3% in the soleus (P < 0.01), a 51.6% reduction in
atrophy associated with
denervation, with little effect on the EDL (9.8 +/- 3.2%
atrophy). Histology showed a preservation of muscle mass and preservation of normal cellular architecture after
Velcade treatment.
Ubiquitin mRNA levels in denervated soleus muscle at the end of the study were significantly elevated 120 +/- 25% above
sham control levels and were reduced to control levels by
Velcade. In contrast,
testosterone proprionate (3 mg/kg sc) did not alleviate
denervation-induced skeletal muscle
atrophy but did prevent
castration-induced levator ani
atrophy, while
Velcade was without effect. These results show that
proteasome inhibition attenuates
denervation-induced
muscle atrophy in vivo in soleus muscles. However, this mechanism may not be operative in all types of
atrophy.