OP0243 AN APPROACH COMBINING TRANSCRIPTOMIC AND TOPOGRAPHIC ANALYSIS REVEALS A POTENTIAL ROLE OF PROTEASOME AND AUTOPHAGY DEREGULATION IN THE PATHOPHYSIOLOGY OF DERMATOMYOSITIS
Authors: Debrut L. , Laverny G. , Mertz P. , Giannini M. , Pizzimenti M. , Charlot A. , Keime C. , Lannes B. , Metzger D. , Geny B. , Sibilia J. , Meyer A. 
Published: May 2021

Background:Dermatomyositis (DM) is a rare autoimmune muscle disease characterized by an atrophy and a type-I interferon signature in perifascicular fibers. We recently showed that muscle mitochondrial dysfunction is also a characteristic of this disease that participates to both decrease exercise capacity and maintenance of inflammation (1). Pathophysiological mechanisms underlying these characteristics are unknown.Objectives:The objective of this study is to reveal the mechanisms underlying the modifications of perifascicular fibers during DM, taking advantage of a method combining transcriptomic and topographical information.Methods:Fourteen patients with recent (<6 months) untreated myositis (DM: n=7, other myositis: n=7) who underwent a biopsy of the deltoid muscle for diagnostic purposes were included. Seven other patients with suspected but not confirmed neuromuscular pathology (normal creatine kinase level, electromyogram and deltoid biopsy) were also included (no myopathy: n=7). Under the control of optical microscopy, perifascicular fibers (about 400 fibers) and endofascicular fibers (about 400 fibers) were microdissected by laser. The transcriptome of endofascicular fibers and perifascicular fibers in all three groups of patients were then obtained by massive sequencing of total messenger RNA. The DAVID database (2) (http://david.abcc.ncifcrf.gov) were used to determine the deregulated molecular pathways in the perifascicular fibers during DM.Results:482 transcripts were differently expressed in perifascicular fibers of patients with DM compared to perifascicular fibers of the 2 other groups (348 overexpressed and 134 underexpressed). The most overexpressed transcripts were involved in the type I interferon response while the most underexpressed transcripts were involved in mitochondria and in proteasome functioning. The study of the transcripts differentially expressed in perifasicular versus endofascicular fibers revealed that there is a physiological perifascicular signature: in patients without myopathy, 83 genes were overexpressed and 54 were underexpressed in perifascicular fibers compared to endofascicular fibers. This physiological perifascicular signature was abolished in patient with myositis (DM and other myositis). In the group of patients with DM (but not other myositis), a specific perifascicular signature (18 genes overexpressed and 10 genes underexpressed in perifascicular fibers compared to endofascicular fibers) was identified. The most deregulated transcripts in DM perifascicular fibers were involved in autophagy/mitophagy, mitochondria and proteasome pathways.Conclusion:In the physiological state, perifascicular fibers are characterized by a different transcriptomic profile from endofascicular fibers. During DM, this physiological perifascicular signature is abolished and replaced by a transcriptomic signature that reveal a potential role of proteasome and autophagy deregulation in the pathophysiology of DM.References:[1]Meyer et al. IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis Acta Neuropathol. 2017;134:655-666.[2]Huang, D. W. et al. The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol 8, R183 (2007).Disclosure of Interests:None declared