Biomarkers

Muscle weakness and inflammation are characteristic features of idiopathic inflammatory myopathies (IIMs), but the molecular pathways that initiate and perpetuate the muscle damage are currently unclear. It is generally thought that IIMs are autoimmune in origin because of the presence of autoantibodies, frequent association with other autoimmune diseases and favorable response in some patients to immunosuppressive therapies. Current literature supports two major immune mediators of muscle damage in myositis: one mediated through T lymphocytes (cytotoxic T cells) directed against muscle fibers, predominating in polymyositis (PM) and inclusion body myositis (IBM), and the other mediated through humoral factors (antibodies and complement) directed against vessels, predominating in patients with dermatomyositis (DM). The relative contribution of immune pathways to disease pathogenesis is undefined. On the other hand, several studies have shown evidence that non-immune processes may also have a role in the pathogenesis of myositis. (1)

ER pathway

In mammalian cells the ER senses and responds to stress through 3 cellular pathways; 1) Inositol-requiring 1 (IRE1), 2) PKR-like ER kinase (PERK), and 3) Activating Transcription Factor 6 (ATF6) . All 3 pathways under normal conditions are kept inactive by glucose regulated protein-78 (GRP78), also referred to as BiP. However, when unfolded proteins accumulate within the ER, BiP is released from the 3 sensors and helps folding of accumulated proteins. This process is generally known as unfolded protein response (UPR) and the release of BiP from IRE1 and PERK leads to homodimerization and release of their cytoplasmic portions. IRE1 then activates the transcription factor X-box binding protein 1 (XBP1) that induces the production of many ER-stress-inducible genes, including members of the Hsp40 family, ER chaperones and XBP1 itself and degradation of other subsets of mRNA. On the other hand, the immediate consequence of PERK activation is translation attenuation through the phosphorylation of the α-subunit of heterotrimeric eukaryotic initiator factor 2 (eIF2α) . The dissociation of BiP from ATF6 permits its translocation to the Golgi where its cytoplasmic portion is cleaved by site-1 and site-2 proteases to generate a cytosolic fragment. These fragments then migrate to the nucleus and induce the expression of genes with ER response elements (ERSE) in their promoters (e.g., GRP78, GRP94, calreticulum6, CHOP, XBP1, Orp 150 (Grp170) and protein disulphide isomerase P5) that in turn help to relieve ER stress. (2)

ER functions

The ER and SR are distinct organelles with different cellular functions. The SR is found in muscle cells and is a specialized form of the ER with a particular distribution of domains and proteins along the contractile unit of muscle fibers that is dedicated to the storage and controlled release of Ca²⁺. On the other hand, the ER is a netlike labyrinth of tubules that is formed from the nuclear envelope by flattened stacks and budding vesicles that performs more complex cellular processes .To understand the role of ER stress in disease conditions, it is important to first understand the function of ER and SR in normal cells. The longitudinal region of SR is specialized in Ca²⁺ uptake by SR/ER Ca²⁺-ATPase pumps (SERCA) and the junctional domain of SR is enriched in the Ca²⁺ releasing channel, ryanodine receptor type 1 (RyR1) and other junctional proteins .Ca²⁺ is stored within the organelle associated with calsequestrin 1, the main calcium buffer of skeletal muscle cells, which also controls the morphological distribution of SR junctional domains, terminal cisternae volume, density and function of RyR through phosphorylation events. Calsequestrin 1 acts as a luminal Ca²⁺ sensor for RyR via its interactions with triadin and junctin. The close relationship between altered expression and dysfunction of calsequestrin in several skeletal and cardiac disorders highlights its role in maintaining Ca²⁺ homeostasis and regulation of muscle contraction. Although the SR stress response is not well studied, it appears that volume alteration triggered by osmotic shock in skeletal fibers induces localized and sustained SR Ca²⁺ release, contributing to skeletal muscle plasticity and/or pathology (3,4)

Recent studies clearly provide evidence that both immune (cell mediated in PM and IBM and humoral in DM) as well as non-immune (ER stress response and autophagy) mechanisms play a role in muscle fiber damage and dysfunction in myostis. It appears that NF-kB bridges the link between these two pathways of muscle dysfunction in all forms of myositis. These data suggest specific drug(s) that target both immune and non-immune pathways would serve as effective therapeutic agents for these disease conditions. (5)

Footnotes

1. Englund P,.Interleukin-1alpha expression in capillaries and major histocompatibility complex class I expression in type II muscle fibers from polymyositis and dermatomyositis patients: important pathogenic features independent of inflammatory cell clusters in muscle tissue. Arthritis Rheum. 2002;46:1044–1055. [PubMed]
2. Raven JF. PERK and PKR: old kinases learn new tricks. Cell Cycle. 2008;7:1146–1150. [PubMed]
3. Shtifman A, .Amyloid-beta protein impairs Ca(2+) release and contractility in skeletal muscle. Neurobiol Aging. 2008 [PMC free article] [PubMed]
4. Rizzuto R. Ca(2+) transfer from the ER to mitochondria: When, how and why. Biochim Biophys Acta. 2009 [PMC free article] [PubMed]
5. Henriques-Pons A, Nagaraju K, Non-immune mechanisms of muscle damage in myositis: Role of the endoplasmic reticulum stress response and autophagy in the disease pathogenesis, Curr Opin Rheumatol. 2009 Nov; 21(6): 581–587.