Endoplasmic Reticulum Stress Is Involved in Muscular Pathogenesis in Idiopathic Inflammatory Myopathies.

Xue Ma,Zhua-Jin Bi,Bi-Tao Bu,Meng-Ge Yang,Su-Qiong Ji,Hua-Jie Gao,Qing Zhang,Li Xu,Yue Li

doi:10.3389/fcell.2022.791986

Abstract

Objectives: Endoplasmic reticulum (ER) stress plays pivotal roles in the regulation of skeletal muscle damage and dysfunction in multiple disease conditions. We postulate the activation of ER stress in idiopathic inflammatory myopathies (IIM). Methods: Thirty-seven patients with immune-mediated necrotizing myopathy (IMNM), 21 patients with dermatomyositis (DM), 6 patients with anti-synthetase syndrome (ASS), and 10 controls were enrolled. The expression of ER stress-induced autophagy pathway was detected using histological sections, Western blot, and real-time quantitative Polymerase Chain Reaction. Results: ER stress-induced autophagy pathway was activated in biopsied muscle of patients with IMNM, DM, and ASS. The ER chaperone protein, glucose-regulated protein 78 (GRP78)/BiP expression in skeletal muscle correlated with autophagy, myofiber atrophy, myonecrosis, myoregeneration, and disease activity in IMNM. Conclusion: ER stress was involved in patients with IIM and correlates with disease activity in IMNM. ER stress response may be responsible for skeletal muscle damage and repair in IIM.

Highlights

Idiopathic inflammatory myopathies (IIM) is currently classified into four major subtypes: dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASS), and sporadic inclusion body myositis based on clinicoseropathological features, myositis-specific antibodies, and transcriptomic signatures (Tanboon et al, 2020)
endoplasmic reticulum (ER) stress is likely to play a role in the pathophysiology of IIM (Nagaraju et al, 2005; Fischer et al, 2019) and may be responsible for muscle damage, but it may paradoxically assist in muscle restoration (Bohnert et al, 2018)
Thirty-seven patients diagnosed with IMNM were enrolled, including 20 patients with anti-signal recognition particle (SRP) antibodies, five patients with anti-hydroxy-3methylglutaryl-coenzyme a reductase (HMGCR) antibodies, and 12 seronegative patients

Summary

Introduction

Idiopathic inflammatory myopathies (IIM) is currently classified into four major subtypes: dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASS), and sporadic inclusion body myositis (sIBM) based on clinicoseropathological features, myositis-specific antibodies, and transcriptomic signatures (Tanboon et al, 2020). The endoplasmic reticulum (ER) stress three sensors, inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6), regulate unfolded protein response (UPR) signaling by recognizing the unfolded proteins (Salminen et al, 2009). These three sensors normally integrate with the chaperone glucose-regulated protein 78 (GRP78)/BiP in the ER lumen. These findings may, not be readily extrapolated to the condition of IMNM

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