title: Overexpression of MHC class I heavy chain protein in young skeletal muscle leads to severe myositis: implications for juvenile myositis.
abstract: Folding and transport of proteins, such as major histocompatibility complex (MHC) class I, through the endoplasmic reticulum (ER) is tightly regulated in all cells, including muscle tissue, where the specialized ER sarcoplasmic reticulum is also critical to muscle fiber function. Overexpression of MHC class I protein is a common feature of many muscle pathologies including idiopathic myositis and can induce ER stress. However, there has been no comparison of the consequences of MHC overexpression in muscle at different ages. We have adapted a transgenic model of myositis induced by overexpression of MHC class I protein in skeletal muscle to investigate the effects of this protein overload on young muscle fibers, as compared with adult tissue. We find a markedly more severe disease phenotype in young mice, with rapid onset of muscle weakness and pathology. Gene expression profiling to compare the two models indicates rapid onset of ER stress in young muscle tissue but also that gene expression of key muscle structural proteins is affected more rapidly in young mice than adults after this insult. This novel model has important implications for our understanding of muscle pathology in dermatomyositis of both adults and children.
authors.affiliation: Rheumatology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, UK.
authors.forename: Charles Kwok-chong
authors.initials: CK
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Knopp
authors.forename: Halima
authors.initials: H
authors.lastname: Moncrieffe
authors.forename: Bhanu
authors.initials: B
authors.lastname: Singh
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Hemlata
authors.initials: H
authors.lastname: Varsani
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D003882:Dermatomyositis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009220:Myositis / Q000209:etiology / Q000276:immunology / Q000378:metabolism*
chemical_list: D015395:Histocompatibility Antigens Class I
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