Activation of the endoplasmic reticulum stress response in autoimmune myositis: Potential role in muscle fiber damage and dysfunction

TLDR

The etiology and pathogenesis of human inflammatory myopathies remain unclear, and studies show that inflammation severity does not consistently correlate with clinical or structural muscle damage, implying nonimmune pathways may contribute. The study aimed to investigate nonimmune pathways in myositis patients and a class I MHC–transgenic mouse model, with the goal of identifying therapeutic targets to interfere with these pathways. The authors examined muscle tissue from human myositis patients and class I MHC–transgenic mice using biochemical, immunohistochemical, and gene expression profiling assays to assess nonimmune pathways. Up‑regulation of class I MHC in skeletal muscle fibers was an early and consistent feature, showing both cell surface and reticular internal reactivity, and the ER stress response, unfolded protein response, and ER overload response pathways were significantly activated in human and mouse muscle tissue, with ectopic expression of wild‑type mouse class I MHC inducing ER stress in C2C12 cells, indicating that ER stress may be a major nonimmune mechanism driving muscle damage and dysfunction in autoimmune myositis.

Abstract

Abstract Objective The etiology and pathogenesis of human inflammatory myopathies remain unclear. Findings of several studies suggest that the degree of inflammation does not correlate consistently with the severity of clinical disease or of structural changes in the muscle fibers, indicating that nonimmune pathways may contribute to the pathogenesis of myositis. This study was undertaken to investigate these pathways in myositis patients and in a class I major histocompatibility complex (MHC)–transgenic mouse model of myositis. Methods We examined muscle tissue from human myositis patients and from class I MHC–transgenic mice for nonimmune pathways, using biochemical, immunohistochemical, and gene expression profiling assays. Results Up‐regulation of class I MHC in skeletal muscle fibers was an early and consistent feature of human inflammatory myopathies. Class I MHC staining in muscle fibers of myositis patients showed both cell surface and a reticular pattern of internal reactivity. The pathways of endoplasmic reticulum (ER) stress response, the unfolded protein response (glucose‐regulated protein 78 pathway), and the ER overload response (NF‐κB pathway) were significantly activated in muscle tissue of human myositis patients and in the mouse model. Ectopic expression of wild‐type mouse class I MHC (H‐2K b ) but not degradable glycosylation mutants of H‐2K b induced ER stress response in C 2 C 12 skeletal muscle cells. Conclusion These results indicate that the ER stress response may be a major nonimmune mechanism responsible for skeletal muscle damage and dysfunction in autoimmune myositis. Strategies to interfere with this pathway may have therapeutic value in patients with this disease.