Muscle atrophy in Limb Girdle Muscular Dystrophy 2A: a morphometric and molecular study
Muscle atrophy in Limb Girdle Muscular Dystrophy 2A: a morphometric and molecular study
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DOI：
10.1111/nan.12034
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发表时间：
2013-12-01
影响因子：
5
通讯作者：
Angelini, C.
中科院分区：
文献类型：
--
作者：
Fanin, M.;Nascimbeni, A. C.;Angelini, C.
目的：calpain-3缺乏症（肌节重构受损）的特殊临床特征和致病机制提示泛素-蛋白酶体降解途径可能在肢体带状肌营养不良2A （LGMD2A）中起关键作用。因此，我们研究了肌肉萎缩和泛素-蛋白酶体和溶酶体-自噬降解途径的作用。方法：我们选择了25名成年男性LGMD2A患者（和7名对照组），使用临床严重程度评分对他们进行分类，通过形态测定法和最重要的萎缩和自噬相关基因（MuRF1, atrogin1, LC3, p62, Bnip3）的蛋白和/或转录表达水平分析肌纤维大小。结果：LGMD2A的肌纤维大小明显低于对照组，且与活检时患者的临床残疾评分显著相关，提示功能性和结构性肌肉损伤是相互依赖的。正如新生儿肌球蛋白免疫标记所评估的那样，绝大多数萎缩纤维起源于不同于再生的机制。与对照组相比，LGMD2A肌肉的MuRF1 （atrogin1）蛋白和MuRF1基因表达水平较高，且MuRF1蛋白水平与肌纤维大小和临床残疾评分均显著相关。LGMD2A肌肉中LC3-II和p62蛋白水平轻微升高，p62和Bnip3基因表达显著上调。结论：在LGMD2A肌肉中，萎缩程序的激活似乎主要依赖于泛素-蛋白酶体系统的诱导，在较小程度上依赖于自噬-溶酶体降解途径。
Aims: The peculiar clinical features and the pathogenic mechanism related to calpain-3 deficiency (impaired sarcomere remodelling) suggest that the ubiquitin-proteasome degradation pathway may have a crucial role in Limb Girdle Muscular Dystrophy 2A (LGMD2A). We therefore investigated muscle atrophy and the role of the ubiquitin-proteasome and lysosomal-autophagic degradation pathways. Methods: We selected 25 adult male LGMD2A patients (and seven controls), classified them using clinical severity score, analysed muscle fibre size by morphometry and protein and/or transcriptional expression levels of the most important atrophy-and autophagy-related genes (MuRF1, atrogin1, LC3, p62, Bnip3). Results: Muscle fibre size was significantly lower in LGMD2A than in controls and it was significantly correlated with patients' clinical disability score recorded at the time of biopsy, suggesting that functional and structural muscle impairment are dependent. The large majority of atrophic fibres originate from a mechanism different from regeneration, as assessed by neonatal myosin immunolabelling. As compared with controls, LGMD2A muscles have higher MuRF1 (but not atrogin1) protein and MuRF1 gene expression levels, and MuRF1 protein levels significantly correlated with both muscle fibre size and clinical disability score. LGMD2A muscles have slightly increased levels of LC3-II and p62 proteins and a significant up-regulation of p62 and Bnip3 gene expression. Conclusions: In LGMD2A muscles the activation of the atrophy programme appeared to depend mainly upon induction of the ubiquitin-proteasome system and, to a lesser extent, the autophagic-lysosomal degradation pathway.