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SOD1-G93A 骨骼肌卫星细胞体外增殖改变。

Altered in vitro proliferation of mouse SOD1-G93A skeletal muscle satellite cells.

机构信息

LAGENBIO-I3A, Aragon's Institute of Health Sciences, University of Zaragoza, Zaragoza, Spain.

出版信息

Neurodegener Dis. 2013;11(3):153-64. doi: 10.1159/000338061. Epub 2012 Jul 10.

Abstract

BACKGROUND

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neurodegenerative disease characterized by ascending muscle weakness, atrophy and paralysis. Early muscle abnormalities that precede motor neuron loss in ALS may destabilize neuromuscular junctions, and we have previously demonstrated alterations in myogenic regulatory factor (MRF) expression in vivo and in the activation of myofiber-associated skeletal muscle satellite cells (SMSCs) in the mouse model of ALS (SOD1-G93A).

METHODS

To elucidate niche dependence versus cell-autonomous mutant SOD1 (mSOD1) toxicity in this model, we measured in vitro proliferation potential and MRF and cyclin gene expression in SMSC cultures derived from fast-twitch extensor digitorum longus and slow-twitch soleus muscles of SOD1-G93A mice.

RESULTS

SMSCs from early presymptomatic (p40) to terminal, semi-paralytic (p120) SOD1-G93A mice demonstrated generally lower proliferation potential compared with age-matched controls. However, induced proliferation was observed in surgically denervated wild-type animals and SOD1-G93A animals at p90, when critical denervation arises. SMSCs from fast and slow muscles were similarly affected by mSOD1 expression. Lowered proliferation rate was generally corroborated with decreased relative MRF expression levels, although this was most prominent in early age and was modulated by muscle type origin. Cyclins controlling cell proliferation did not show modifications in their mRNA levels; however, the expression of cyclin-dependent kinase inhibitor 1A (Cdkn1a), which is known to promote myoblast differentiation, was decreased in SOD1-G93A cultures.

CONCLUSIONS

Our data suggest that the function of SMSCs is impaired in SOD1-G93A satellite cells from the earliest stages of the disease when no critical motor neuron loss has been described.

摘要

背景

肌萎缩侧索硬化症(ALS)是最常见的成年起病的神经退行性疾病,其特征为肌肉无力、萎缩和瘫痪进行性加重。在 ALS 中,运动神经元丢失之前的早期肌肉异常可能会使运动神经元丧失稳定性,我们之前已经证明了肌生成调节因子(MRF)在体内的表达以及肌纤维相关的骨骼肌卫星细胞(SMSCs)在 ALS 小鼠模型(SOD1-G93A)中的激活发生了改变。

方法

为了阐明在该模型中,龛依赖性与细胞自主型突变 SOD1(mSOD1)毒性之间的关系,我们测量了源自快速抽搐伸肌趾长肌和慢速抽搐比目鱼肌的 SMSC 培养物的体外增殖潜力以及 MRF 和细胞周期蛋白基因表达。

结果

与年龄匹配的对照组相比,源自早期无症状(p40)到终末期,半瘫痪(p120)SOD1-G93A 小鼠的 SMSC 通常具有较低的增殖潜力。然而,在手术去神经的野生型动物和 SOD1-G93A 动物中(在出现关键去神经时)观察到诱导性增殖。mSOD1 的表达对快肌和慢肌的 SMSC 都有类似的影响。较低的增殖率通常与相对 MRF 表达水平降低相符,尽管这在早期更为明显,并且受到肌肉类型起源的调节。控制细胞增殖的细胞周期蛋白的 mRNA 水平没有改变;然而,已知可促进成肌细胞分化的细胞周期蛋白依赖性激酶抑制剂 1A(Cdkn1a)的表达在 SOD1-G93A 培养物中降低。

结论

我们的数据表明,在尚未描述关键运动神经元丢失的情况下,SOD1-G93A 卫星细胞从疾病的最早阶段就已经出现 SMSC 功能障碍。

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