A precise knowledge of the role of subunits of the 19S complex and the PA28 regulator, which associate with the
20S proteasome and regulate its
peptidase activities, may contribute to design new therapeutic approaches for preventing muscle wasting in human diseases. The
proteasome is mainly responsible for the muscle wasting of
tumor-bearing and unweighted rats. The expression of some
ATPase (MSS1, P45) and non
ATPase (P112-L, P31) subunits of the 19S complex, and of the two subunits of the PA28 regulator, was studied in such atrophying muscles. The
mRNA levels for all studied subunits increased in unweighted rats, and analysis of MSS1
mRNA distribution profile in polyribosomes showed that this subunit entered active translation. By contrast, only the
mRNA levels for MSS1 increased in the muscles from
cancer rats. Thus, gene expression of the
proteasome regulatory subunits depends on a given catabolic state.
Torbafylline, a
xanthine derivative which inhibits
tumor necrosis factor production, prevented the activation of
protein breakdown and the increased expression of
20S proteasome subunits in
cancer rats, without reducing the elevated MSS1
mRNA levels. Thus, the increased expression of MSS1 is regulated independently of
20S proteasome subunits, and did not result in accelerated proteolysis.