Inhibition of GSK‐3 activity with lithium (LiCl) in vitro attenuates sepsis‐induced changes in muscle protein turnover

Abstract

Our study determined whether in vitro treatment of skeletal muscle with LiCl, a GSK-3 inhibitor, would reverse both the sepsis-induced increase in protein degradation and inhibition of protein synthesis. Sepsis decreased GSK-3 phosphorylation and increased GSK-3 activity, under basal conditions. Sepsis increased muscle protein degradation, with a concomitant increase in atrogin-1 and MuRF1 mRNA and 26S proteasome activity. Incubation of septic muscle with LiCl reversed the increased GSK-3 activity and decreased proteolysis to nonseptic values, but only partially reduced proteasome activity and did not diminish atrogene mRNA. LiCl did not ameliorate the sepsis-induced increase in LC3-II (eg., autophagy). In contrast, LiCl increased protein synthesis only in nonseptic muscle. The inability of septic muscle to respond to LiCl was independent of its ability to reverse the sepsis-induced increase in eIF2Be phosphorylation and decreased eIF2B activity, but was associated with the continued suppression of mTOR kinase. Our data suggest in vitro LiCl which inhibited GSK-3 activity: a) reversed the sepsis-induced increase in proteolysis, but only in part by a reduction in the ubiquitin-proteasome pathway and not by a reduction in autophagy; and b) was ineffective at reversing the sepsis-induced decrease in muscle protein synthesis. This Li resistant state appears mediated at the level of mTOR and not eIF2/eIF2B.