Unravelling inclusion body myositis using a patient-derived fibroblast model

IF 9.1 1区 医学
Judith Cantó-Santos, Laura Valls-Roca, Ester Tobías, Francesc Josep García-García, Mariona Guitart-Mampel, Anna Esteve-Codina, Beatriz Martín-Mur, Mercedes Casado, Rafael Artuch, Estel Solsona-Vilarrasa, José Carlos Fernandez-Checa, Carmen García-Ruiz, Carles Rentero, Carlos Enrich, Pedro J. Moreno-Lozano, José César Milisenda, Francesc Cardellach, Josep M. Grau-Junyent, Glòria Garrabou
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引用次数: 1

Abstract

Background

Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established biomarkers or effective treatments are available, partly due to the lack of validated disease models.

Methods

We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA-seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls.

Results

Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P-value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three-fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time-course autophagosome formation (LC3BII 39% reduced, P-value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P-value < 0.05) and function (30.2%-decrease in respiration, 45.6%-decline in enzymatic activity (P-value < 0.001), 14.3%-higher oxidative stress, 135.2%-increased antioxidant defence (P-value < 0.05), 11.6%-reduced mitochondrial membrane potential (P-value < 0.05) and 42.8%-reduced mitochondrial elongation (P-value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8-fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis.

Conclusions

These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.

使用患者来源的成纤维细胞模型解开包涵体肌炎
包涵体肌炎(IBM)是一种炎症性肌病,临床表现为近端和远端肌肉无力,肌肉组织病理学表现为炎症浸润、边缘空泡和线粒体改变。关于IBM病因学的知识很少,而且没有确定的生物标志物或有效的治疗方法,部分原因是缺乏经过验证的疾病模型。方法我们对IBM患者(n = 14)和健康对照(n = 12)的成纤维细胞(按年龄和性别配对)的IBM肌肉病理特征进行了转录组学和功能验证。结果包括mRNA-seq,以及患者和对照组之间的功能性炎症、自噬、线粒体和代谢变化。结果IBM与对照成纤维细胞基因表达谱显示778个差异表达基因(p值adj <0.05),与炎症、线粒体、细胞周期调节和代谢有关。在功能上,在IBM成纤维细胞中观察到炎症谱增加,上清细胞因子分泌增加(增加三倍)。考虑到基础蛋白介质,自噬减少了18.4%,自噬体形成的时间过程(LC3BII)减少了39%,p值<0.05),以及自噬体显微评价。线粒体的遗传含量降低了33.9%,p值<0.05)和功能(30.2%-呼吸下降,45.6%-酶活性下降)(p值<0.001), 14.3%-氧化应激升高,135.2%-抗氧化防御增强(p值<0.05),线粒体膜电位降低11.6% (p值<0.05),线粒体延伸率降低42.8% (p值<0.05))。在代谢物水平上,有机酸增加了1.8倍,氨基酸谱保守。与疾病演变相关,氧化应激和炎症成为预后的潜在标志。这些发现证实了IBM患者外周组织中存在分子干扰,并提示患者衍生的成纤维细胞是一种有希望的疾病模型,最终可能会推广到其他神经肌肉疾病。我们还在IBM中识别与疾病进展相关的新分子参与者,为深化疾病病原学、鉴定新型生物标志物或标准化仿生平台以分析临床前研究的新治疗策略奠定了基础。
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来源期刊
Journal of Cachexia, Sarcopenia and Muscle
Journal of Cachexia, Sarcopenia and Muscle Medicine-Orthopedics and Sports Medicine
自引率
12.40%
发文量
0
期刊介绍: The Journal of Cachexia, Sarcopenia, and Muscle is a prestigious, peer-reviewed international publication committed to disseminating research and clinical insights pertaining to cachexia, sarcopenia, body composition, and the physiological and pathophysiological alterations occurring throughout the lifespan and in various illnesses across the spectrum of life sciences. This journal serves as a valuable resource for physicians, biochemists, biologists, dieticians, pharmacologists, and students alike.
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