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 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 findings: 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.

Summary: 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.

Figure 1

ER and SR interactions within mammalian cells. The ER establishes important physical contact with other organelles and plasma membrane (upper panel). The contact of SR with the membrane permits the rapid reload with Ca²⁺ from the extracellular environment and is mediated by oligomers of STIM-1 (a Ca²⁺ sensor) and the channel Orai (panel 1). The ER stress response called UPR relies on the release of Bip from the stress sensors when unfolded proteins accumulate in the organelle. Without Bip, IRE1 and PERK form homodymers and their cytoplasmic portions are free to interact with XBP1 and eIF2α to increase the transcription of housekeeping genes and translation attenuation, respectively. The Bip-free ATF6 in targeted to the Golgi where its cytoplasmic portion is released to migrate to the nucleus for transcriptional activation (panel 2). SR (and ER) and mitochondria also make intimate contact, which is very important for cell function, although only the Ca²⁺ exchange is represented in panel 3. This exchange is mediated by RyR, VDAC, and Mitochondrial Ca²⁺ uniport (MCU) for Ca²⁺ influx from SR to mitochondria. For influx from mitochondria to SR the players are an undefined channel (?, in figure), VDAC and SERCA. SERCA also mediates Ca²⁺ influx from cytoplasm to SR (panel 3). For ER/autophagy pathway there is the export of unfolded proteins through the Sec61 translocon for degradation by the proteasome, in a process called UPR, and/or the activation of autophagy (upper panel). The Atg1 kinase homologue, unc-51-like kinase (ULK1) in mammals, is one of the initial molecules in autophagy and is silenced by Bcl-2, located on the ER, and m-TOR (panel 4). Then the PI3K complex is formed, composed by Beclin-1, P150, phosphorylated Vps34 (a class III phosphatidylinositol 3-kinase (PI3K)), and UVRAG in mammals. The next step represented in panel 4 is the elongation of the phagophore through the addition of LC3-PE (phosphatidylethanolamine) for lysosomal degradation of sequestered components in the closed autophagosome.

Figure 2

Immune and non immune mechanisms of muscle fiber damage in myositis. ER, endoplasmic reticulum; UPR, unfolded protein response; MHC, major histocompatibility complex; PM polymyositis; IBM, inclusion body myositis; DM, dermatomyositis.