Overexpression of MHC class I heavy chain protein in young skeletal muscle leads to severe myositis: implications for juvenile myositis.
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.
Li
Charles Kwok-chong
CK
Rheumatology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, UK.
Knopp
Paul
P
Moncrieffe
Halima
H
Singh
Bhanu
B
Shah
Sonia
S
Nagaraju
Kanneboyina
K
Varsani
Hemlata
H
Gao
Bin
B
Wedderburn
Lucy R
LR
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*
D015395:Histocompatibility Antigens Class I
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14296-301
16186509
Muscle Nerve. 2007 Oct;36(4):455-65
17554798
BMC Dev Biol. 2008 Feb 20;8:18
18289368
Front Biosci. 2000 Sep 01;5:D750-67
10966875
Hum Pathol. 1989 Mar;20(3):224-31
2470663
Muscle Nerve. 1983 Oct;6(8):574-80
6646160
Development. 2003 Dec;130(24):6089-99
14597575
Rheumatology (Oxford). 2006 Oct;45(10):1255-60
16567354
J Cell Biol. 2005 May 23;169(4):555-60
15897261
J Biol Chem. 2007 May 18;282(20):15000-10
17383968
Arthritis Rheum. 2007 Sep;56(9):3132-7
17763420
Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1411-20
16617122
Cell Mol Life Sci. 2008 Mar;65(6):862-94
18038217
Arthritis Rheum. 2005 Jun;52(6):1824-35
15934115
Biochem J. 1999 Apr 1;339 ( Pt 1):1-10
10085220
Arthritis Rheum. 2002 Apr;46(4):1044-55
11953983
J Cell Biol. 1995 Feb;128(3):273-82
7844142
Traffic. 2007 Mar;8(3):184-94
17319799
Dev Dyn. 2008 Feb;237(2):403-10
18213585
Cell. 2003 Jun 27;113(7):841-52
12837243
Ann Neurol. 1988 Jan;23(1):64-72
3278673
Clin Exp Immunol. 1986 Feb;63(2):450-8
2421951
Biochem Biophys Res Commun. 2001 Jan 12;280(1):407-14
11162531
J Cell Biol. 2004 Aug 2;166(3):347-57
15277541
PLoS One. 2008 Feb 13;3(2):e1609
18270596
Nature. 2004 Jun 24;429(6994):841-7
15215856
J Exp Med. 2005 Feb 21;201(4):591-601
15728237
Arthritis Rheum. 2008 Feb;58(2):547-55
18240224
Dev Dyn. 1992 Jan;193(1):34-9
1311614
BMC Immunol. 2008 Jul 31;9:43
18671865
Biotechnol Bioeng. 2003 Jan 5;81(1):56-65
12432581
J Neuroimmunol. 2002 Apr;125(1-2):42-50
11960639
Biochem Cell Biol. 2006 Dec;84(6):881-9
17215875
Am J Pathol. 2004 Jan;164(1):1-7
14695312
Neurology. 1991 Jul;41(7):1128-32
1906147
Clin Exp Immunol. 1998 Sep;113(3):407-14
9737670
Ann Neurol. 2005 May;57(5):664-78
15852401
Nature. 2004 Jun 24;429(6994):834-40
15215855
Arthritis Rheum. 2000 Mar;43(3):541-9
10728746
Rheum Dis Clin North Am. 1997 Aug;23(3):619-55
9287380
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9209-14
10922072
Nature. 2007 Mar 15;446(7133):333-7
17310145
J Immunol. 2002 Apr 15;168(8):4154-63
11937576
Cell Struct Funct. 2007;32(1):41-50
17507765
J Biol Chem. 2008 Mar 28;283(13):8453-61
18222920
Nat Rev Immunol. 2006 Dec;6(12):919-29
17124513
Stat Appl Genet Mol Biol. 2004;3:Article3
16646809
FASEB J. 2007 Sep;21(11):2994-3003
17435177
J Cell Biol. 1997 Dec 1;139(5):1157-68
9382863
J Rheumatol. 2004 Mar;31(3):605-9
14994413
Best Pract Res Clin Rheumatol. 2004 Jun;18(3):345-58
15158745
Am J Physiol Cell Physiol. 2001 Oct;281(4):C1285-90
11546666
Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9
16432136