Early onset of inflammation and later involvement of TGFβ in Duchenne muscular dystrophy
Early onset of inflammation and later involvement of TGFβ in Duchenne muscular dystrophy
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DOI：
10.1212/01.wnl.0000173836.09176.c4
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发表时间：
2005-09-27
期刊：
影响因子：
9.9
通讯作者：
Hoffman, EP
中科院分区：
文献类型：
--
作者：
Chen, YW;Nagaraju, K;Hoffman, EP
目的：探讨假肥大型肌营养不良症（DMD）发病阶段特异性诱导分子病理学通路。研究方法：我们使用来自胎儿、婴儿（8至10个月）和有症状的DMD患者（5至12岁）以及年龄和性别匹配的对照组的肌肉进行mRNA分析。我们进行免疫组织化学，以确定在蛋白质水平和蛋白质定位的变化。结果如下：DMD肌肉组织树突状细胞的活化、Toll样受体7的表达和核因子-κ B通路的强诱导在出生后不久发生。两个肌肉萎缩途径，atrogin-1和myostatin，在疾病的任何阶段都没有被诱导。正常肌肉的糖酵解和氧化代谢能力随着年龄的增长而积累，但这种积累在DMD中失败。转化生长因子（TGF）-β通路在有症状的患者中被强烈诱导，TGF β II型受体和凋亡信号调节激酶1蛋白在成熟DMD肌纤维亚群上表达。我们的数据显示了人类肌营养不良蛋白缺陷肌肉的阶段特异性重塑，炎症途径在症状前阶段占主导地位，TGF β的急性激活和代谢途径的失败在症状后阶段占主导地位。疾病
Objective: To identify stage-specific induction of molecular pathology pathways in Duchenne muscular dystrophy (DMD). Methods: We performed mRNA profiling using muscles from fetopsies, infants (aged 8 to 10 months), and symptomatic patients (aged 5 to 12 years) with DMD, and age- and sex-matched controls. We performed immunohistochemistry to determine changes at the protein level and protein localization. Results: Activated tissue dendritic cells, expression of toll-like receptor 7, and strong induction of nuclear factor-kappa B pathways occurred soon after birth in DMD muscle. Two muscle wasting pathways, atrogin-1 and myostatin, were not induced at any stage of the disease. Normal muscle showed accumulation of glycolytic and oxidative metabolism capacity with increased age, but this accumulation failed in DMD. The transforming growth factor (TGF)-beta pathway was strongly induced in symptomatic patients, with expression of TGF beta type II receptor and apoptosis signal-regulating kinase 1 proteins on subsets of mature DMD myofibers Conclusions: Our data show stage-specific remodeling of human dystrophin-deficient muscle, with inflammatory pathways predominating in the presymptomatic stages and acute activation of TGF beta and failure of metabolic pathways later in the disease.