Published online before print August 21, 2009

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(American Journal of Pathology. 2009;175:1030-1040.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090196

Overexpression of MHC Class I Heavy Chain Protein in Young Skeletal Muscle Leads to Severe Myositis

Implications for Juvenile Myositis

Charles Kwok-chong Li^*, Paul Knopp^*, Halima Moncrieffe^*, Bhanu Singh, Sonia Shah, Kanneboyina Nagaraju, Hemlata Varsani^*, Bin Gao^* and Lucy R. Wedderburn^*

From the Rheumatology Unit,^* Institute of Child Health, and the Department of Bioinformatics, University College London, London, United Kingdom; the Department of Pathology and Infectious Diseases, the Royal Veterinary College, Hertfordshire, United Kingdom; and the Research Center for Genetic Medicine, Children’s National Medical Center, Washington DC

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.