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,Lucy R Wedderburn

doi:10.2353/ajpath.2009.090196

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.

Highlights

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 critical to muscle fiber function
To investigate whether overexpression of MHC class I in skeletal muscle at a young age would alter either disease phenotype or kinetics of onset, we compared mice in which MHC class I induction was initiated at 21 days (HT-E) to those in which induction was at 35 days (HT-L)
We have adapted our previous model of myositis, in which self MHC class I heavy chain is overexpressed in muscle, by overexpressing the MHC class I protein from a younger age

Summary

Introduction

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 critical to muscle fiber function. Gene expression profiling to compare the two models indicates rapid onset of ER stress in young muscle tissue and 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. We and others have demonstrated that overexpression of MHC class I occurs early in both adult and juvenile dermatomyositis, even in the absence of inflammatory cell infiltrate.[7,8] The conditional transgenic model of myositis (‘HT’) where self MHC class I is overexpressed in skeletal muscle, exhibits clinical, biochemical, histological, and immunological features that parallel. MHC class l expression is normally down-regulated during muscle differentiation from myoblast to myotube, and expression remains low in mature myofibers, a process that is tightly regulated by myoblast regulatory factors including MyoD, Myf[5], and myogenin.[13]

Objectives

Methods

Results

Conclusion