Structural and functional alterations of muscle fibres in the novel mouse model of facioscapulohumeral muscular dystrophy
Structural and functional alterations of muscle fibres in the novel mouse model of facioscapulohumeral muscular dystrophy
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DOI：
10.1113/jphysiol.2007.141481
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发表时间：
2007-11-01
影响因子：
5.5
通讯作者：
Bottinelli, Roberto
中科院分区：
文献类型：
--
作者：
D'Antona, Giuseppe;Brocca, Lorenza;Bottinelli, Roberto
最近，我们通过选择性过表达FRG 1（FSHD的候选基因）在骨骼肌中产生了面肩肱型肌营养不良症（FSHD）的小鼠模型。FRG-1小鼠的肌肉没有显示出任何质膜缺陷，这表明FSHD的一种新的发病机制。在这里，我们研究的结构和功能的肌纤维从三个线的小鼠过表达FRG 1在不同的水平：FRG 1-低，FRG 1-中，FRG 1-高。对FRG 1-low和FRG 1-med小鼠的已鉴定类型的肌纤维的横截面积（CSA）、比力（Po/CSA）和最大缩短速度（V-o）进行了分析，发现其低于WT小鼠。快的纤维，特别是2B型纤维（最快的类型）优先参与营养不良的过程中表现出更大的力赤字比I型（慢）的纤维。与后一观察结果一致，与WT肌肉相比，三个FRG 1系的几种肌肉的MHC同种型分布显示出向较慢的MHC同种型转变。此外，快速肌肉表现出更明显的组织学恶化，更大的萎缩和更高的百分比的中央有核纤维比比目鱼肌，小鼠最慢的肌肉。有趣的是，单个肌纤维的CSA、Po/CSA和Vo的损失以及MHC同种型向较慢表型转变可以被认为是肌营养不良症（MD）的早期体征。事实上，它们也在FRG 1低小鼠中发现，这些小鼠在体内没有显示出任何功能受损，在体外没有显示出肌肉大小受损，在比目鱼肌中也发现了它们，比目鱼肌具有完全保留的形态。本研究提供了一种主要人类MD之一的新型鼠模型中肌纤维结构和功能的详细表征，并表明大多数MD共同的营养不良过程的基本特征，如肌纤维收缩力的内在丧失，快纤维的优先参与和向慢肌表型的转变可以独立于血浆的明显改变而发生膜的
We recently generated a mouse model of facioscapulohumeral muscular dystrophy (FSHD) by selectively overexpressing FRG1, a candidate gene for FSHD, in skeletal muscle. The muscles of the FRG-1 mice did not show any plasmamembrane defect suggesting a novel pathogenetic mechanism for FSHD. Here, we study structure and function of muscle fibres from three lines of mice overexpressing FRG1 at different levels: FRG1-low, FRG1-med, FRG1-high. Cross-sectional area (CSA), specific force (Po/CSA) and maximum shortening velocity (V-o) of identified types of muscle fibres from FRG1-low and FRG1-med mice were analysed and found to be lower than in WT mice. Fast fibres and especially type 2B fibres (the fastest type) were preferentially involved in the dystrophic process showing a much larger force deficit than type I (slow) fibres. Consistent with the latter observation, the MHC isoform distribution of several muscles of the three FRG1 lines showed a shift towards slower MHC isoforms in comparison to WT muscle. Moreover, fast muscles showed a more evident histological deterioration, a larger atrophy and a higher percentage of centrally nucleated fibres than the soleus, the slowest muscle in mice. Interestingly, loss in CSA, Po/CSA and Vo of single muscle fibres and MHC isoform shift towards a slower phenotype can be considered early signs of muscular dystrophy (MD). They were, in fact, found also in FRG1-low mice which did not show any impairment of function in vivo and of muscle size in vitro and in soleus muscles, which had a completely preserved morphology. This study provides a detailed characterization of structure and function of muscle fibres in a novel murine model of one of the main human MDs and suggests that fundamental features of the dystrophic process, common to most MDs, such as the intrinsic loss of contractile strength of muscle fibres, the preferential involvement of fast fibres and the shift towards a slow muscle phenotype can occur independently from obvious alterations of the plasma membrane.