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

Abstract

Purpose of review-Recent literature in inflammatory myopathies suggests that both immune (cell-mediated and humoral) and non-immune (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 findings-Recent data highlights 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.Summary-Current data indicate that the ER stress, NF-kB pathway and autophagy are active in the skeletal muscle of myositis patients, and the pro-inflammatory NF-kB pathway connects the immune and non-immune pathways of muscle damage. The relative contributions of each of these pathways to muscle fiber damage are presently unclear. Therefore further defining the role of these pathways in disease pathogenesis should help to design effective therapeutic agents for these diseases.

Anti-SAE antibodies in autoimmune myositis: Identification by unlabelled protein immunoprecipitation in an Italian patient cohort

“…Sumoylation alteration could cause protein accumulation in endoplasmic reticulum (ER), inducing an ER stress response. ER stress response activation has been demonstrated in autoimmune myositis and proposed as a non-immune mechanism of muscle fiber damage and dysfunction (Dalakas, 2012;Henriques-Pons and Nagaraju, 2009;Nagaraju et al, 2005;Vattemi et al, 2004;Vitadello et al, 2010).…”

Pathogenesis, classification and treatment of inflammatory myopathies

“…5 Finally, ER stress might contribute to muscle dysfunction by inducing muscle fiber apoptosis or autophagic cell death. 87 …”

Inflammatory myopathy associated with statins: report of three cases

“…This is in agreement with the findings of Nagaraju et al [38], who supposed that muscle fiber death in myositis could be induced by not only immune attack (caused by cytotoxic T lymphocytes or autoantibodies) but also the endoplasmic reticulum stress response, which leads to intracellular homeostasis disturbance. The endoplasmic reticulum stress response leads to cell death via apoptosis and autophagy, with the latter becoming even more important recently [39].…”