Immunoproteasome subunit β5i promotes perifascicular muscle atrophy in dermatomyositis by upregulating RIG-I

Abstract

Background Perifascicular atrophy is a unique pathological hallmark in dermatomyositis (DM)-affected muscles; however, the mechanism underlying this process remains unclear. In this study, we aimed to investigate the potential role of the immunoproteasome subunit β5i and retinoic acid-inducible gene-I (RIG-I) in DM-associated muscle atrophy.Methods The expression of β5i and RIG-I in the muscles of 16 patients with DM was examined by PCR, western blotting and immunohistochemistry. The associations between β5i and RIG-I expression levels and muscle disease severity were evaluated. Lentivirus transduction was used to overexpress β5i in human skeletal muscle myoblasts (HSMMs) and consequent cell functional changes were studied in vitro.Results β5i and RIG-I expression in the muscle of patients with DM was significantly increased and closely associated with muscle disease severity. Immunohistochemistry and immunofluorescence analyses showed the marked colocalised expression of β5i and RIG-I in perifascicular myofibres. β5i overexpression in HSMMs significantly upregulated RIG-I, the muscle atrophy marker MuRF1, type I IFN-related proteins (MxA and IFNβ) and NF-κB pathway-related proteins (pIκBα, pIRF3 and pNF-κBp65). In addition, the viability of HSMMs decreased significantly after β5i overexpression and was partly recovered by treatment with a β5i inhibitor (PR957). Moreover, activation of RIG-I by pppRNA upregulated IFNβ and MuRF1 and reduced the cell viability of HSMMs.Conclusion The immunoproteasome subunit β5i promotes perifascicular muscle atrophy in DM via RIG-I upregulation; our findings suggest a pathomechanistic role of β5i and RIG-I in DM-associated muscle damage, highlighting these components as potential therapeutic targets for the treatment of DM.