ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers.
ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers.
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DOI：
10.1371/journal.pone.0177649
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Brandan E
中科院分区：
文献类型：
--
作者：
Gonzalez D;Contreras O;Rebolledo DL;Espinoza JP;van Zundert B;Brandan E
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，患者的上、下运动神经元退化，导致肌肉萎缩、瘫痪，最终死于呼吸衰竭。几项研究表明，骨骼肌有助于疾病进展；然而，分子机制仍然难以捉摸。纤维化是骨骼肌慢性损伤条件下的常见特征，如由肌肉营养不良或去神经支配引起的骨骼肌损伤。然而，纤维化诱导的确切机制和这种病理反应的细胞基础尚不清楚。我们发现细胞外基质（ECM）成分在症状性hSOD1G93A小鼠骨骼肌中增加，hSOD1G93A是一种广泛使用的ALS小鼠模型。这些小鼠还显示TGF-β1 mRNA水平升高，总Smad3蛋白水平升高，p-Smad3阳性核。此外，有症状的hSOD1G93A小鼠骨骼肌中血小板衍生生长因子受体-α (PDGFRα)、Tcf4和α-平滑肌肌动蛋白（α-SMA）水平升高。此外，纤维/脂肪源性祖细胞（FAPs）是ECM成分的主要生产者，在这些致病条件下也增加。因此，FAPs和ECM成分在疾病的症状阶段比症状前阶段更丰富。我们提供的证据表明，在有症状的hSOD1G93A小鼠骨骼肌中观察到的纤维化伴随着TGF-β信号的诱导，并且FAPs可能参与引发纤维化反应。在症状性hSOD1G93A小鼠骨骼肌间质细胞中观察到p-Smad3阳性细胞与PDGFRα共定位。最后，靶向促纤维化因子如TGF-β、CTGF/CCN2和血小板衍生生长因子（PDGF）信号通路可能是改善多种退行性疾病肌肉功能的合适治疗途径。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motoneurons degenerate leading to muscle wasting, paralysis and eventually death from respiratory failure. Several studies indicate that skeletal muscle contributes to disease progression; however the molecular mechanisms remain elusive. Fibrosis is a common feature in skeletal muscle under chronic damage conditions such as those caused by muscular dystrophies or denervation. However, the exact mechanisms of fibrosis induction and the cellular bases of this pathological response are unknown. We show that extracellular matrix (ECM) components are augmented in skeletal muscles of symptomatic hSOD1G93A mice, a widely used murine model of ALS. These mice also show increased TGF-β1 mRNA levels, total Smad3 protein levels and p-Smad3 positive nuclei. Furthermore, platelet-derived growth factor receptor-α (PDGFRα), Tcf4 and α-smooth muscle actin (α-SMA) levels are augmented in the skeletal muscle of symptomatic hSOD1G93A mice. Additionally, the fibro/adipogenic progenitors (FAPs), which are the main producers of ECM constituents, are also increased in these pathogenic conditions. Therefore, FAPs and ECM components are more abundant in symptomatic stages of the disease than in pre-symptomatic stages. We present evidence that fibrosis observed in skeletal muscle of symptomatic hSOD1G93A mice is accompanied with an induction of TGF-β signaling, and also that FAPs might be involved in triggering a fibrotic response. Co-localization of p-Smad3 positive cells together with PDGFRα was observed in the interstitial cells of skeletal muscles from symptomatic hSOD1G93A mice. Finally, the targeting of pro-fibrotic factors such as TGF-β, CTGF/CCN2 and platelet-derived growth factor (PDGF) signaling pathway might be a suitable therapeutic approach to improve muscle function in several degenerative diseases.