SEPSIS-INDUCED INCREASE IN MUSCLE PROTEOLYSIS IS BLOCKED BY SPECIFIC PROTEASOME INHIBITORS

Recent studies suggest that sepsis stimulates ubiquitin-dependent prot ein breakdown in skeletal muscle. The 20S proteasome is the catalytic core of the ubiquitin-dependent proteolytic pathway. We tested the eff ects in vitro of the proteasome inhibitors N-acetyl-L-leucinyl-L-leuci nal-L-norleucinal (LLnL) and lactacystin on protein breakdown in incub ated muscles from septic rats. LLnL resulted in a dose-and time-depend ent inhibition of protein breakdown in muscles from septic rats. Lacta cystin blocked both total and myofibrillar muscle protein breakdown. I n addition to inhibiting protein breakdown, LLnL reduced muscle protei n synthesis and increased ubiquitin mRNA levels, probably reflecting i nhibited proteasome-associated ribonuclease activity. Inhibited muscle protein breakdown caused by LLnL or lactacystin supports the concept that the ubiquitin-proteasome pathway plays a central role in sepsis-i nduced muscle proteolysis. The results suggest that muscle catabolism during sepsis may be inhibited by targeting specific molecular mechani sms of muscle proteolysis.