Denervation Induced Muscle Atrophy

PURPOSE: Ubiquitin-proteasome pathway (UPP) is one of the main protein degradation pathways during muscle atrophy. The 20S core proteasome is responsible for proteolysis in UPP, which is composed of several key components, including α and β catalytic subunits. However, how these key components participate in protein degradation in denervation induced muscle atrophy is not fully understood. The first goal was to characterize proteasome function and composition of the catalytic subunits in denervated skeletal muscle. The second goal was to explore the non-immune function of immunoproteasome, specifically how it regulates proteolysis. METHODS: Adult male C57BL6 wild type (WT) and immunoproteasome LMP7-/-/MECL1-/- (L7M1) mice underwent tibial nerve transection on the right hindlimb for either 7 or 14 days, while control mice did not undergo surgery. Proteasome activity (caspase-, chymotrypsin-, and trypsin- like), and protein content of the proteasome (β1, β5 and β2) and the immunoproteasome subunits (LMP2, LMP7 and MECL1) were determined in the gastrocnemius muscle. RESULTS: Denervation induced significant atrophy and was accompanied by increased activities and protein content of the proteasome catalytic subunits. Although denervation resulted in a similar degree of muscle atrophy between strains, the mice lacking two immunoproteasome subunits showed different responses in the extent and duration of proteasome characteristics, including proteasome activities and content of β1, β5 and LMP2. CONCLUSIONS: The results indicate denervation induced muscle atrophy is associated with increased proteolysis and an upregulation of proteasome catalytic subunits. In addition, it appears that the immunoproteasome may facilitate UPP by influencing proteasome activities.