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Background: Heat shock proteins (Hsps) are chaperones playing important roles in skeletal muscle physiology, adaptation to exercise or stress, and activation of inflammatory cells
Objectives: The aim of our study was to assess Hsp90 expression in muscle biopsies and plasma of patients with idiopathic inflammatory myopathies (IIM) and to characterize its association with IIM-related features.
Methods: Total of 277 patients with IIM (198 females, 79 males; mean age 54.8; disease duration 4.1 years; DM, 104/PM, 108/CADM, 31/IMNM, 25) and 157 healthy individuals (92 females, 65 males; mean age 47.0) were included in plasma analysis. Muscle biopsy samples (PM, DM, IMNM, myodystrophy, myasthenia gravis) were stained for Hsp90α (Thermo Fisher Scientific, USA) and Hsp90β (Abcam, UK). Plasma Hsp90 was measured by ELISA kit (eBioscience, Vienna, Austria). The cytokines/chemokines were analysed by using Bio-Plex Pro TM human Cytokine 27-plex Assay (BIO-RAD, California, USA.Data are presented as median(IQR).
Results: In muscle biopsies, Hsp90 expression of both subunits (alpha and beta) was higher in IIM than in controls. Increased Hsp90 was detected in perifascicular degenerating and regenerating fibers, inflammatory cells (DM, PM), and necrotic and regenerating fibers (IMNM). Plasma Hsp90 levels were increased in IIM patients compared to healthy controls (55.9 (46.9 – 62.5)vs 9.76(7.5 – 13.8), p<0.0001), and in individual subgroups of IIM vs. healthy controls (DM-22.01(14.1 – 41.2), PM-19.7(14.3 – 42.2), CADM-18.9(11.7 – 29.7), IMNM-19.6(16.3 – 45.5), p<0.0001 for all). Hsp90 was higher in males compared to females (p=0.040) and in patients with ILD (p=0.003), cardiac involvement (p=0.004), dysphagia (p=0.018) and presence of anti-Ro52 (p=0.036). Hsp90 levels in all patients positively correlated with muscle enzymes (Tab.1). Hsp90 was associated with disease activity and skeletal muscle involvement (Tab.1). Out of all clinical parameters listed in above-mentioned univariate analysis, in multiple regression analysis Hsp90 levels in IIM patients were significantly affected by muscle enzymes only (p<0.0001, β=0.345). Furthermore, Hsp90 positively correlated with some crucial cytokines involved in pathogenesis of myositis (Tab. 1).
| Clinical parameters | Spearman’s r | p – value |
|---|---|---|
| LDH; AST; ALT | 0.554; 0.383; 0.181 | < 0.0001; < 0.0001; 0.003 |
| PtDGA; PhDGA; MITAX; MYOACT | 0.223; 0.217; 0.175; 0.159 | < 0.001; < 0.001; 0.004; 0.012 |
| Pulmonary disease activity | 0.201 | 0.001 |
| Muscle disease activity | 0.146 | 0.018 |
| MMT8, total score; m. biceps brachii; m. gluteus maximus; m. iliopsoas | -0.126; -0.125; -0.159; -0.143 | 0.042; 0.043; 0.011; 0.023 |
| MDI – Myositis damage index – severity | 0.150 | 0.041 |
| Current Prednisone equivalent dose | 0.183 | 0.006 |
| Cytokines: IL-1b; IL-2; IL-4; IL-6; IFN-γ | 0.188; 0.269; 0.190; 0.182; 0.229 | 0.002; < 0.0001; 0.002; 0.003; < 0.0001 |
Conclusion: We demonstrate increased Hsp90 expression in IIM muscle biopsy samples, specifically in inflammatory cells, degenerating, regenerating and/or necrotic fibers. Increased Hsp90 plasma levels in IIM patients are associated with disease activity and damage, and with the involvement of proximal skeletal muscles, heart and lungs.
Acknowledgments: Supported by AZV-16-33542A, MHCR 023728 and SVV – 260373.
Disclosure of Interests: Hana Štorkánová: None declared, Sabina Oreska: None declared, Maja Špiritović: None declared, Barbora Heřmánková: None declared, Olga Kryštůfková: None declared, Heřman Mann: None declared, Martin Komarc: None declared, Josef Zámečník: None declared, Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Jiří Vencovský: None declared, Ladislav Šenolt: None declared, Michal Tomcik: None declared