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• W2170828910 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. 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. The idiopathic inflammatory muscle diseases are a group of autoimmune conditions affecting patients of all age groups, characterized by proximal muscle weakness, skeletal muscle damage and systemic involvement. It has been observed that despite obvious similarities, there are also differences that distinguish myositis in adults and children. Childhood myositis may show a very rapid onset, is not associated with malignancy, is more often complicated by vasculitic systemic features, and carries a better prognosis of full muscle power and functional recovery if treatment is rapid and adequate.1Rider LG Miller FW Classification and treatment of the juvenile idiopathic inflammatory myopathies.Rheum Dis Clin North Am. 1997; 23: 619-655Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 2Wedderburn LR Li CK Paediatric idiopathic inflammatory muscle disease.Best Pract Res Clin Rheumatol. 2004; 18: 345-358Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Juvenile dermatomyositis is the most common of myositis of childhood onset, and is associated with considerable morbidity and even mortality.3Huber AM Lang B LeBlanc CM Birdi N Bolaria RK Malleson P MacNeil I Momy JA Avery G Feldman BM Medium- and long-term functional outcomes in a multicenter cohort of children with juvenile dermatomyositis.Arthritis Rheum. 2000; 43: 541-549Crossref PubMed Scopus (219) Google Scholar, 4McCann LJ Juggins AD Maillard SM Wedderburn LR Davidson JE Murray KJ Pilkington CA The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)–clinical characteristics of children recruited within the first 5 years.Rheumatology. 2006; 45: 1255-1260Crossref PubMed Scopus (185) Google Scholar Class I major histocompatibility complex (MHC) protein is overexpressed in skeletal muscle from all types of idiopathic inflammatory muscle diseases, including juvenile dermatomyositis and also in other muscle pathologies including inclusion body myositis.5Isenberg DA Rowe D Shearer M Novick D Beverley PC Localization of interferons and interleukin 2 in polymyositis and muscular dystrophy.Clin Exp Immunol. 1986; 63: 450-458PubMed Google Scholar, 6Karpati G Pouliot Y Carpenter S Expression of immunoreactive major histocompatibility complex products in human skeletal muscles.Ann Neurol. 1988; 23: 64-72Crossref PubMed Scopus (276) Google Scholar, 7Li CK Varsani H Holton JL Gao B Woo P Wedderburn LR MHC Class I overexpression on muscles in early juvenile dermatomyositis.J Rheumatol. 2004; 31: 605-609PubMed Google Scholar It is unclear whether MHC overexpression is directly causal in muscle damage. 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.7Li CK Varsani H Holton JL Gao B Woo P Wedderburn LR MHC Class I overexpression on muscles in early juvenile dermatomyositis.J Rheumatol. 2004; 31: 605-609PubMed Google Scholar, 8Englund P Nennesmo I Klareskog L Lundberg IE 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: 1044-1055Crossref PubMed Scopus (76) Google Scholar 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 some of those of human disease.9Nagaraju K Raben N Loeffler L Parker T Rochon PJ Lee E Danning C Wada R Thompson C Bahtiyar G Craft J Hooft Van Huijsduijnen R Plotz P Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies.Proc Natl Acad Sci USA. 2000; 97: 9209-9214Crossref PubMed Scopus (241) Google Scholar Following upregulation of transgenic self MHC class I at 5 to 6 weeks of age, female mice develop muscle histological changes from about 3 months of age, reduced locomotor activity, muscle enzyme (creatine kinase and glutamic-oxaloacetic transaminase) rise at 5 months, and histological features of muscle damage at 5 to 6 months. MHC class I is expressed at low levels in healthy mature muscle fibers, but can be up-regulated by inflammatory cytokines such as tumor necrosis factor-α or interferons.10Emslie-Smith AM Arahata K Engel AG Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.Hum Pathol. 1989; 20: 224-231Abstract Full Text PDF PubMed Scopus (306) Google Scholar, 11Mantegazza R Hughes SM Mitchell D Travis M Blau HM Steinman L Modulation of MHC class II antigen expression in human myoblasts after treatment with IFN-gamma.Neurology. 1991; 41: 1128-1132Crossref PubMed Google Scholar, 12Nagaraju K Raben N Merritt G Loeffler L Kirk K Plotz P A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli.Clin Exp Immunol. 1998; 113: 407-414Crossref PubMed Scopus (133) Google Scholar MHC class I is expressed at high levels in muscle progenitor cells, myoblasts. 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, Myf5, and myogenin.13Perry RL Rudnick MA Molecular mechanisms regulating myogenic determination and differentiation.Front Biosci. 2000; 5: D750-D767Crossref PubMed Google Scholar The ER and Golgi of all cells, including skeletal muscle, have a stringent ‘quality control’ sensor system to detect and deal with abnormalities of protein expression, folding and assembly. Abnormal levels of expression, misfolding or abnormal glycosylation of ER resident proteins may lead to ER stress.14Cudna RE Dickson AJ Endoplasmic reticulum signaling as a determinant of recombinant protein expression.Biotechnol Bioeng. 2003; 81: 56-65Crossref PubMed Scopus (90) Google Scholar, 15Schroder M Endoplasmic reticulum stress responses.Cell Mol Life Sci. 2008; 65: 862-894Crossref PubMed Scopus (503) Google Scholar ER stress responses are classified into two major pathways: the unfolded protein response, and the ER overload response. The unfolded protein response reduces levels of misfolded or overexpressed proteins, by inducing transcription of ER chaperones, reducing protein synthesis, and enhancing degradation of misfolded proteins via an ubiquitin-proteasome system, ER-associated degradation. Prolonged unfolded protein response leads ultimately to cell death through apoptosis. In skeletal muscle, ER stress plays a role in normal development and homeostasis. ER stress genes are up-regulated during the transition from myoblast to myotube, when some cells die by apoptosis, and others survive and fuse to form multinucleate fibers.16Nakanishi K Sudo T Morishima N Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development.J Cell Biol. 2005; 169: 555-560Crossref PubMed Scopus (157) Google Scholar Skeletal muscle has a highly specialized ER, the sarcoplasmic reticulum, where Ca2+ binding proteins play a pivotal role in signals critical to muscle contraction and function, so may be highly sensitive to triggers that disrupt ER/sarcoplasmic reticulum function and Ca2+ homeostasis. ER stress has been implicated in several muscle diseases, including inclusion body myositis, dermatomyositis and muscle disuse atrophy.17Hunter RB Mitchell-Felton H Essig DA Kandarian SC Expression of endoplasmic reticulum stress proteins during skeletal muscle disuse atrophy.Am J Physiol Cell Physiol. 2001; 281: C1285-C1290PubMed Google Scholar, 18Vattemi G Engel WK McFerrin J Askanas V Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle.Am J Pathol. 2004; 164: 1-7Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 19Nagaraju K Casciola-Rosen L Lundberg I Rawat R Cutting S Thapliyal R Chang J Dwivedi S Mitsak M Chen YW Plotz P Rosen A Hoffman E Raben N Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction.Arthritis Rheum. 2005; 52: 1824-1835Crossref PubMed Scopus (261) Google Scholar, 20Zhang K Kaufman RJ The unfolded protein response: a stress signaling pathway critical for health and disease.Neurology. 2006; 66: S102-S109Crossref PubMed Scopus (504) Google Scholar ER stress also has a role in the HT model where MHC class I protein is overexpressed in skeletal muscle.19Nagaraju K Casciola-Rosen L Lundberg I Rawat R Cutting S Thapliyal R Chang J Dwivedi S Mitsak M Chen YW Plotz P Rosen A Hoffman E Raben N Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction.Arthritis Rheum. 2005; 52: 1824-1835Crossref PubMed Scopus (261) Google Scholar However, there have been no previous studies comparing the response of skeletal muscle to specific stress triggers at different ages. The aim of this study was to compare the consequences of upregulation of MHC class I protein in skeletal muscle of young and adult mice. Strikingly we find that the overexpression of MHC class I heavy chain protein at a young age leads to a more rapid and severe disease phenotype. This study provides new insights into age-specific differences in the responses of young and adult muscle to injury, as well as generating a novel model, which will be a highly efficient system for further investigation of the mechanisms of myositis. This project was performed with ethical approval, and a full UK Home Office License. The generation of conditional MHC class I transgenic mice was as described previously.9Nagaraju K Raben N Loeffler L Parker T Rochon PJ Lee E Danning C Wada R Thompson C Bahtiyar G Craft J Hooft Van Huijsduijnen R Plotz P Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies.Proc Natl Acad Sci USA. 2000; 97: 9209-9214Crossref PubMed Scopus (241) Google Scholar Briefly, overexpression of autologous MHC class I heavy chain in skeletal muscle was induced by expression of transgenic H-2Kb controlled by the tetracycline/doxycyline transactivator (Tta), under the muscle-specific promoter, creatine kinase. Tissue-specific transgene expression occurs after withdrawal of doxycycline from the drinking water. Disease induction was performed in females only. For this study mice of the existing model were denoted HT-L. To mimic activation during juvenile stage of muscle development, doxycycline was given to female nursing mice only until weaning of offspring, inducing MHC class I heavy chain transgene induction from 21 days of age. Mice in this group were designated HT-E. HT-E mice were compared with the mice treated according to the original protocol (HT-L) in which doxycycline was withdrawn at 35 days, with consequent up-regulation of MHC class I heavy chain. Single transgenic females who received doxycycline for the same period of time, served as controls for histological analysis and gene expression analysis. Double transgenic (HT) littermates maintained on doxycycline served as controls for strength and mortality assessment. Mice were genotyped by PCR on genomic DNA by standard methods. Primers to detect the transgenes were H-2Kb forward: 5′-TCGAGTTTACCACTCCCTATCAG-3′, H-2Kb reverse: 5′-GATCTGACGGTTCACTAAACGAG-3′ and Tta forward: 5′-CGCTGTGGGGCATTTTACTTTAG-3′ and Tta reverse: 5′-CATGTCCAGATCGAAATCGTC-3′. Mice were observed every other day for appearance, behavioral changes, and disease phenotype including muscle weakness. A scoring system of disease was devised according to veterinary regulations and subjects were culled when license regulations required this. To compare phenotype, histology, and gene expression, mice of each model (HT-E, HT-L, and age matched littermate controls) were sacrificed at pre-defined time points. Quadriceps femoris and gastrocnemius muscles were dissected immediately after culling. Tissues were either snap frozen in liquid nitrogen and cryopreserved, or fixed in 10% buffered formalin. Staining for morphological assessment was by standard H&E method (Sigma Haverhill, UK). Immunohistochemistry was performed on 8-μm cryosections after acetone fixation, by standard two-antibody method with visualization of avidin-peroxidase by 3,3′ diaminobenzidine, (Dako Glostrup, Denmark). Antibodies used were: monoclonal anti-MOMA-2, which recognizes cells of the macrophages/monocyte lineage (Dako), monoclonal anti-murine CD3 (eBioscience San Diego, CA), polyclonal rabbit anti-murine Ubiquitin (Dako), and isotype controls matching the primary antibody (Serotec, Raleigh, NC). Secondary antibodies were biotinylated donkey anti-rabbit-IgG (Chemicon, Billerica, MA) or biotinylated rabbit anti-rat-IgG (Vector Laboratories, Burlingame CA). Morphological features were scored by a veterinary pathologist blinded to identification or clinical status of the animals (B.S.) for features of degeneration, regeneration, and muscle fiber changes. Briefly, muscle degeneration was characterized by sarcoplasmic swelling, pallor, and vacuolization. Necrotic myofibers showed sarcoplasmic hypereosinophilia with loss of cross-striations, fragmentation, and nuclear pyknosis, karyorrhexis, and karyolysis.21Leninger JR Skeletal muscle.in: Maronpot RR Boorman GA Gaul BW Pathology of the Mouse. Cache River Press, Vienna, IL1999: 637Google Scholar A score of 0 was given for no lesion or changes, 1 for where scattered single myofibers were affected, 2 for where scattered small groups of myofibers affected, 3 for wide spread small groups of myofibers affected, and 4 for where confluent groups of myofibers were affected. Inflammatory features consisted of inflammatory cells (predominantly macrophages, and fewer lymphocytes and plasma cells) infiltration. The microscopic features of regenerative changes include satellite cell activation/migration, myofibers with basophilic cytoplasm, nuclear internalization, and large nuclei with prominent nucleoli. A score of 0 was given for no changes, 1 for mild changes, 2 for moderate changes, 3 for marked changes, and 4 for severe/wide-spread changes. The scoring process for both degenerative and inflammatory features was performed twice at least 1 month apart for verification. Mice from three groups (each n = 3), HT-E, HT-L, and controls, were selected for gene expression comparison. HT-E (early) were removed from doxycycline at 21 days, and sacrificed at 35 days of age, after 2 weeks of transgene expression. HT-L (late) mice were maintained on doxycycline until 35 days9Nagaraju K Raben N Loeffler L Parker T Rochon PJ Lee E Danning C Wada R Thompson C Bahtiyar G Craft J Hooft Van Huijsduijnen R Plotz P Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies.Proc Natl Acad Sci USA. 2000; 97: 9209-9214Crossref PubMed Scopus (241) Google Scholar and sacrificed at 49 to 50 days of age. Single transgenic littermate controls were age, sex-matched, maintained on doxycycline, and sacrificed as the HT-E group. Total RNA was extracted from 100 mg of quadriceps muscle using RNAB reagent (Campro Scientific, Berlin, Germany). RNA integrity and purity were confirmed by Nanoreader 600 Assay (Agilent, Palo Alto, CA). Five μg total RNA was used to prepare cRNA for each gene profile experiment. cRNA probe was generated by in vitro transcription, and fragmented biotinylated probe hybridized to murine MOE 430 v2.0 genechips using standard Affymetrix protocols (Santa Clara, CA). Genechip quality and experimental reproducibility were assessed using SimplyAffy package v2.6.0. The statistical significance of the survival difference between groups of mice was calculated by Cox regression analysis of a Kaplan-Meier series. Quantitative data from histological scoring of muscle sections were expressed as the mean ± SD. Data from the scores of this muscle analysis were compared by the Mann Whitney test in SPSS. The raw mRNA gene expression data were normalized and summarized using GC Robust Microarray average.22Wu Z Irizarry R Gentleman R Murillo FM Spencer FC Model-based background adjustment for oligonucleotide expression arrays.J Am Stat Assoc. 2004; 99: 909-917Crossref Scopus (1238) Google Scholar Differentially expressed genes were identified using the Limma analysis package23Smyth GK Linear models and empirical bayes methods for assessing differential expression in microarray experiments.Stat Appl Genet Mol Biol. 2004; 3: 3Crossref Scopus (8979) Google Scholar in Bioconductor. Genes that had a Benjamini-Hochberg corrected P value <0.05 were considered to be differentially expressed. The full raw gene expression profiling data are available on the Geo database (http://www.ncbi.nlm.nih.gov/geo/, accession number GSE14997; last accessed August 14, 2009) and are compliant with minimum information about a microarray experiment (MIAME) guidelines. 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). HT-E mice were found to develop weakness far more rapidly than HT-L mice. Behavioral changes including hunched posture and reduction in spontaneous movement such as climbing to the top of the cage, occurred at a much earlier stage in HT-E mice, typically at about 1 month, and in some cases as early as 14 days, after doxycycline withdrawal. The survival of mice of HT-E model (n = 35), mice of HT-L model (n = 37) and control mice (n = 10) were followed until death or until culling was required due to severe weakness (Figure 1). Survival time of transgenic mice was significantly reduced in HT-E compared with the HT-L group (P < 0.0001). To compare the features and kinetics of muscle pathology induced in the ‘early’ mouse model of myositis, HT-E, HT-L, and control mice were culled at different times after transgene induction, (2, 4 and 8 to 12 weeks) n = 4 mice per group. This timed analysis confirmed that changes in skeletal muscles were observed more rapidly after overexpression of MHC class I in the HT-E than the HT-L model. Microscopic changes observed included early vacuolar degeneration, segmental fiber necrosis, variable fiber size, centralized myonuclei, and an inflammatory cell infiltration (composed of cells of myeloid origin) detectable in skeletal muscle of HT-E mice (Figure 2A). Results from scoring of the degenerative features confirmed an early difference in histological changes in HT-E compared with HT-L model, Figure 2B. Four weeks after transgene induction, differences in severity scores between HT-E and L gastrocnemius muscle were statistically significant (P = 0.028), and showed a similar trend in quadriceps (P = 0.0578). By 8 weeks, there was no difference between HT-E and HT-L models in severity scores in either gastrocnemius or quadriceps scores. As described in the original myositis model, the inflammatory infiltrate in the HT-E model was predominantly of a macrophage/myeloid lineage with no detectable T or B cell lymphocytic component (Figure 2C). Postmortem examinations were performed 6 weeks after transgene activation on those HT-E mice that had demonstrated behavioral deterioration such as reduced spontaneous activity and hunched posture. These postmortem examinations revealed skeletal muscle degeneration and necrosis compared with controls, but no abnormalities were found in other organs including diaphragmatic muscles, lungs, kidneys, liver, and spleen (data not shown). Gene expression analysis was performed on muscle tissue from three groups of mice: HT-E and HT-L mice (each after only 14 days of transgene expression), and age matched littermate controls. Unsupervised hierarchical clustering of samples revealed that gene expression in the standard myositis model (HT-L) was largely unaltered from control mice (Figure 3A). In contrast gene expression of the HT-E mice was noted to cluster separately from both control mice and the HT-L model. Transcripts of MHC class I H-2K, detected with probes that do not distinguish between the endogenous and transgenic MHC class l expression, were up-regulated in both HT-E and HT-L mice, as compared with that in controls, as expected. There was no significant difference in H-2K expression between HT-E or HT-L models, confirming that the transgene is equally expressed in both models (data not shown). There was no significant difference in expression of creatine kinase, an important validation, since the transgene is regulated by this muscle specific promoter. Analysis of gene expression data from the three groups of mice revealed many genes with significantly altered expression to a level of P < 0.05, after correction for multiple testing. Analysis of genes that were significantly altered in the HT-E model compared with their age matched controls revealed 48 probe sets from 41 genes that were differentially expressed (Table 1). Of these 48 ‘top’ differentially expressed probes, 36 were also significantly altered in HT-E when compared with HT-L model, with parallel direction and fold changes. Of those 12 probes that were not significantly different between HT-E and HT-L mice, but did differ between HT-E and controls, 4 were specific for MHC class l H-2K (equally up-regulated in HT-E and HT-L). Figure 3B shows hierarchical clustering analysis (using Euclidian distance and complete linkage) of these 48 differentially expressed probes in the HT-E model compared with HT-L and to control mice. Gene expression in the HT-L model clustered closely to control mice while gene expression in HT-E mice clustered apart from either HT-L mice or controls.Table 1Differentially Expressed Genes in the HT-E Model Compared with Controls and with the HT-L ModelEarly (HT-E) vs. controlEarly (HT-E) vs. late (HT-L)Probe set IDSymbolLog fold changeFold changeP value↠Log fold changeFold changeP value1452754_at5730592L21Rik↑2.937.640.0042↑2.776.810.00631426852_x_atNov↓−1.59−3.020.0060↓−1.47−2.770.00711426534_a_atArfgap3↑2.114.320.0089↑2.214.630.00711427746_x_atH2-K1↑5.1034.270.0138NS1421018_at1110018J18Rik↑1.022.030.0138NS1425348_a_atSrprb↑1.292.440.0138↑1.422.680.00911418974_atBlzf1↑1.102.140.0138↑0.551.460.03671418899_atUfm1↑0.871.830.0138↑0.981.980.00911425336_x_atH2-K1↑4.1417.690.0138NS1424948_x_atH2-K1↑5.3941.870.0138NS1439030_atGmppb↑1.542.900.0138↑1.893.700.00911453749_at2610507I01Rik↑2.405.260.0138NS1440002_atRnmt↑0.491.400.0153↑0.511.430.01041418355_atNucb2↑1.422.680.0153↑1.332.520.01121434341_x_at1110020P15Rik↑2.244.730.0176NS1416234_atAA959742↑1.362.560.0199↑1.122.170.01671416497_atPdia4↑2.244.740.01992.365.120.01041423793_atD2Ertd391e↑1.132.190.0199NS1451175_atSpcs3↑1.623.070.0199↑1.342.540.01671434744_atYrdc↑1.362.560.0226↑1.472.770.01041424194_atRcsd1↓−0.76−1.690.0233↓−0.99−1.990.00911434340_at1110020P15Rik↑5.1635.740.0233NS1455839_atUgcgl1↑1.432.690.0233↑1.262.390.01671453677_a_atDerl3↑4.0716.780.0262↑4.0616.660.01451425242_at1810006K21Rik↑0.671.590.0271↑0.611.530.01671450318_a_atP2ry2↓−0.64−1.560.0278↓−0.76−1.690.01041418973_atBlzf1↑0.971.950.0278NS1426851_a_atNov↓−1.28−2.430.0321↓−1.12−2.170.02121423151_atDnajb11↑2.044.120.0323↑1.753.360.02171437358_atWdfy1↓−0.79−1.730.0352NS1428112_atArmet↑3.5811.990.0371↑2.837.100.02651438040_a_atTra1↑2.144.400.0371↑2.284.850.01571448549_a_atDpagt1↑1.242.360.0384↑1.032.040.02421436774_atSel1 hours↑1.142.200.0403↑0.831.780.03431456947_atPafah1b1↑0.981.970.0415NS1440549_atAtp6v1 hours↑0.451.360.0415↑0.461.370.01671450534_x_atH2-K1↑7.29156.370.0415NS1453718_atBcl2l12↑0.401.320.0428↑0.361.280.02251426479_a_atTnrc5↑1.122.170.0428↑1.212.320.01671422980_a_atBet1l↑1.593.000.0428↑2.114.330.01041448769_atSlc35b1↑1.633.100.0428↑1.212.320.03711417267_s_atFkbp11↑2.686.420.0428↑3.319.890.01231424818_atAlg12↑1.623.070.0428↑1.673.190.01811455838_at4933406A14Rik↑0.401.320.0428↑0.361.280.02321417119_atZfpl1↑1.152.220.0428↑1.542.910.01041420868_s_atTmed2↑0.741.670.0436↑0.831.780.01641416696_atD17Wsu104e↑1.723.290.0462↑2.565.890.01041418250_atArfl4↓−1.23−2.350.0494↓−1.19−2.280.0225 Open table in a new tab Analysis of significantly altered genes in the HT-E compared with HT-L model revealed 549 probes (representing 504 genes) that were significantly altered (P < 0.05), of which 273 probes demonstrated a ≥twofold change in expression. These 273 probes are listed in the Supplementary Data Table (please see Supplemental Table at http://ajp.amjpathol.org). Analysis of genes that differed between the HT-E and HT-L models suggested several functional pathways that were altered after only two weeks of MHC class l overexpression in young muscle. The first group of genes altered in HT-E compared with HT-L mice were genes intrinsic to protein transport, folding, processing, glycosylation, or other ER and Golgi functions (Table 2). These included proteins that ensure correct folding such as protein disulphide isomerases,24Ferrari DM Soling HD The protein disulphide-isomerase family: unravelling a string of folds.Biochem J. 1999; 339: 1-10Crossref PubMed Scopus (432) Google Scholar Ca2+ dependent chaperones calreticulin, Tra1 (also known as Grp94),15Schroder M Endoplasmic reticulum stress responses.Cell Mol Life Sci. 2008; 65: 862-894Crossref PubMed Scopus (503) Google Scholar and members of the Hsp40 family, binding partners of Hsp70 chaperones. Many of these are known to be increased during ER stress.25Maattanen P Kozlov G Gehring K Thomas DY ERp57 and PDI: multifunctional protein disulfide isomerases with similar domain architectures but differing substrate-partner associations.Biochem Cell Biol. 2006; 84: 881-889Crossref PubMed Google Scholar The demonstration of Hsp expression parallels our own previous findings in patients with juvenile dermatomyositis, in whom Hsp60 and Hsp70 proteins are highly expressed in muscle.26Elst EF Klein M de Jager W Kamphuis S Wedderburn LR van der Zee R Albani S Kuis W Prakken BJ Hsp60 in inflamed muscle tissue is the target of regulatory autoreactive T cells in patients with juvenile dermatomyositis.Arthritis Rheum. 2008; 58: 547-555Crossref PubMed Scopus (33) Google ScholarTable 2Genes Up-Regulated in the HT-E Model that Relate to ER Function, Protein Transport, Golgi Function, the SNARE Complex, or UbiquitinationHT-E vs. HT-LHT-E vs. controlFunctional roleSymbol (alternative)NameFold changeP valueFold changeP valueER protein transportSrprbSignal recognition particle receptor, B subunit*Genes had 2 or more differentially expressed probe sets. For these genes the data for the probe set with the highest fold change is shown.3.420.02252.440.0138ER protein transportTmed9Transmembrane emp24 protein transport domain containing 9*Genes had 2 or more differentially expressed probe sets. For these genes the data for the probe set with the highest fold change is shown.3.420.0167NSER protein transportTmed2Transmembrane emp24" @default.
• W2170828910 created "2016-06-24" @default.
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• W2170828910 date "2009-09-01" @default.
• W2170828910 modified "2023-10-17" @default.
• W2170828910 title "Overexpression of MHC Class I Heavy Chain Protein in Young Skeletal Muscle Leads to Severe Myositis" @default.
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