Nonimmune mechanisms of muscle damage in myositis: role of the endoplasmic reticulum stress response and autophagy in the disease pathogenesis

Abstract

Recent literature in inflammatory myopathies suggests that both immune (cell-mediated and humoral) and nonimmune [endoplasmic reticulum (ER) stress and autophagy] mechanisms play a role in muscle fiber damage and dysfunction. This review describes these findings and discusses their relevance to disease pathogenesis and therapy. Recent studies highlight the role of ER stress response, especially the roles of hexose-6-phosphate dehydrogenase and ER-anchored RING finger E3 ligase in the activation of unfolded protein response and the formation of vacuoles and inclusions in myopathies. Several studies investigated the link between inflammation and the beta-amyloid-associated muscle fiber degeneration and loss of muscle function. Likewise, the roles of ER stress and autophagy in skeletal muscle damage have been explored in multiple muscle diseases. Current data indicate that the ER stress, nuclear factor-kappaB pathway and autophagy are active in the skeletal muscle of myositis patients, and the proinflammatory nuclear factor-kappaB pathway connects the immune and nonimmune pathways of muscle damage. The relative contributions of each of these pathways to muscle fiber damage are currently unclear. Therefore, further defining the role of these pathways in disease pathogenesis should help to design effective therapeutic agents for these diseases.