Immune Response and Mitochondrial Metabolism Are Commonly Deregulated in DMD and Aging Skeletal Muscle
Immune Response and Mitochondrial Metabolism Are Commonly Deregulated in DMD and Aging Skeletal Muscle
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DOI：
10.1371/journal.pone.0026952
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发表时间：
2011-11-09
期刊：
影响因子：
3.7
通讯作者：
Pereon, Yann
中科院分区：
文献类型：
--
作者：
Baron, Daniel;Magot, Armelle;Pereon, Yann
Duchenne肌营养不良症(DMD)是一个复杂的过程，涉及初级遗传损伤下游的多条途径，导致致命的肌肉退化。肌肉老化是一个多因素的神经肌肉过程，其特征是肌肉再生受损导致进行性萎缩。我们假设这些慢性萎缩的情况可能根据组织重塑在转录水平上共享特定的肌源性适应性反应。来自四名年轻DMD和四名老年受试者的肌肉活检参照了一组来自没有任何神经肌肉疾病的年轻受试者的肌肉活检，并通过专门的表达微阵列进行了探索。我们确定了528个差异表达基因(在2745个被分析的基因中)，其中328个可以通过对涉及骨骼肌DMD和衰老的公共微阵列数据集的详尽荟萃分析来验证。在验证的328个共表达基因中，50%在两组中具有相同的表达谱，对应于免疫/纤维化反应和线粒体代谢。将这些观察到的元特征用大量的公共数据集概括起来，加强了我们的结果，因为它们也可以在其他病理过程和不同的生理条件下被识别。集中在这两种萎缩条件下的共同基因特征，我们观察到候选转录因子的基序丰富，这些转录因子可能协调免疫/纤维化反应(ETS1，IRF1，NF1)或线粒体代谢(ESRRA)。至少在一定程度上，它们表达的失控可能是启动慢性肌肉萎缩的相同转录组变化的原因。这项研究表明，不同的病理生理过程可能共享与特定转录因子相关的共同基因反应和途径。
Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors.