Figure 3

Non-immune mechanisms of muscle damage and weakness. MHC class I overexpression on myofibers make muscle susceptible for CD8 T-cell mediated cytotoxicity as well as susceptible to endoplasmic reticulum stress-induced cell death. MHC class I accumulation in endoplasmic reticulum induces stress responses (unfolded protein response and endoplasmic reticulum overload response (EOR)) [27, 94–98]. Induction of EOR activates downstream NF-kB pathway leading to pro-inflammatory cytokine production and reduction in new muscle formation by inhibiting MyoD. It also induces cell death mechanisms via the activation of caspases 12, 3 and 7 as well as calpain pathways (Step A) [27]. Innate cytokines, mitochondrial energy-related metabolic pathways, and purine nucleotide pathways are interconnected in myositis muscle. For instance, IL-1 reduces the production of nitric oxide (NO) and causes mitochondrial dysfunction by affecting NADH reductase and succinate CoQ [99–102]. Likewise, unknown cytokines reduce expression of rate-limiting enzymes of the purine nucleotide cycle and of AMPD1 in skeletal muscle. This acquired deficiency of APMD1 causes muscle weakness and fatigue in myositis (Step B) [103]. Activation of TRAIL forms autophagosomes and induces autophagy (Step C) [104]. TLR signaling leads to inflammasome activation, IL-1 secretion and pyroapoptosis in the affected muscle. There are active interactions between autophagy, ER stress, and inflammasome and purine nucleotide pathways. Even though all these pathways are interconnected, we have represented them as linear pathways in this illustration for easier understanding. Thus, several non-immune and metabolic pathways directly and indirectly contribute to muscle weakness and damage in myositis.