PROTEASOME BLOCKERS INHIBIT PROTEIN BREAKDOWN IN SKELETAL-MUSCLE AFTER BURN INJURY IN RATS

1. Burn injury stimulates ubiquitin-dependent protein breakdown in ske letal muscle. The 20S proteasome is the proteolytic core of the 26S pr oteasome that degrades ubiquitin conjugates. We examined the effects o f the proteasome inhibitors N-acetyl-L-leucinyl-L-leucinal-L-norleucin al (LLnL), lactacystin and beta-lactone on protein breakdown in muscle s from burned rats. 2. A full-thickness burn of 30% total body surface area was inflicted on the back of rats. Control rats underwent a sham procedure. After 24 h, extensor digitorum longus muscles were incubat ed in the absence or presence of 20S proteasome blocker and protein tu rnover rates and ubiquitin mRNA levels were determined. 3. LLnL result ed in a dose- and time-dependent inhibition of total protein breakdown in incubated muscles from burned rats. Lactacystin and beta-lactone b locked both total and myofibrillar muscle protein breakdown. In additi on to inhibiting protein breakdown, LLnL increased ubiquitin mRNA leve ls, possibly reflecting inhibited proteasome-associated RNase activity . 4. Inhibited muscle protein breakdown caused by LLnL, lactacystin an d beta-lactone supports the concept that the ubiquitin-proteasome path way plays a central role in burn-induced muscle proteolysis. Because t he proteasome has multiple important functions in the cell, in additio n to regulating general protein breakdown, further studies are needed to test the role of proteasome blockers in the treatment or prevention of muscle catabolism.