Abstract
Skeletal muscle atrophy is induced by raised glucocorticoid (GC) levels and reduced insulin/IGF‐1‐Akt signaling. Glycogen synthase kinase‐3 beta (GSK‐3b) is a downstream kinase of Akt involved in regulation of muscle protein turnover.We hypothesized that muscle GC receptor (GR) and GSK‐3b are required for muscle atrophy in response to pulmonary inflammation.Control, muscle specific‐GR (mGRKO) or ‐GSK‐3b (mGSK‐3bKO) mice were subjected to intra‐tracheal LPS instillation to induce acute pulmonary inflammation.Increases in circulating corticosterone levels following IT‐LPS were similar in control, mGRKO and mGSK‐3KO mice, but accompanied by substantial muscle atrophy in control mice only. Accordingly, increases in mRNA transcripts encoding effectors of the Ub 26S‐proteasome (MuRF1 and Atrogin‐1) and autophagy‐lysosomal (Bnip3, LC3b) systems were strongly attenuated in muscle of mGRKO or mGSK‐3KO mice. Interestingly, increased expression of GC‐sensitive genes (Glul, KLF15 and REDD1) and FOXO1 and ‐3a following IT‐LPS, was suppressed in skeletal muscle of GRKO and GSK‐3KO mice. This dependency of GR signaling on GSK‐3b was confirmed in cultured muscle cells.We conclude that pulmonary inflammation‐induced muscle atrophy is dependent on an intact GSK‐3b‐GR signaling axis.Support: Dutch Astma Foundation (3.2.07.017) and Dutch Top Institute Pharma (T1–201)
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call