The role of FHL1 in Emery-Dreifuss and Reducing Body Myopathies

描述(申请人提供)：最近，在包括减少性躯体肌病(RBM)和Emery-Dreifuss肌营养不良症(EDMD)在内的罕见肌病患者中发现了四个半LIM结构域1(FHL1)基因的突变。一些实验证据支持FHL1在骨骼肌肥大和萎缩中起重要作用的观点。FHL1在胚胎和出生后骨骼肌生长以及牵张诱导的骨骼肌肥大中上调。相反，FHL1在废弃诱导的肌肉萎缩中下调。最近有报道称，FHL1在C2C12细胞中过表达可促进成肌细胞融合，导致肌管肥大。FHL1转基因在小鼠骨骼肌中的过表达促进肥大并刺激氧化纤维类型的产生。为了了解FHL1在体内的作用，我们建立了一个FHL1所有亚型都被无处不在地去除的小鼠系(FHL1-空小鼠)。我们对FHL1缺失小鼠骨骼肌的初步研究表明，我们的模型显示出一种营养不良的表型，模仿了在人类患者中观察到的肌病的一些生理和形态方面。这证实了FHL1在肌肉生长和动态平衡中发挥的重要作用。然而，导致不同形式肌病的人类突变是由导致质和量变化的突变引起的，但不是完全丧失FHL1蛋白。这项建议的总体目标是了解FHL1在骨骼肌生长和动态平衡中所起的作用，并了解为什么FHL1的不同突变会导致不同的肌病。我们将通过充分表征目前可用的FHL1缺失小鼠品系的表型，并通过创建和详细表征另外两个将通过基因打靶引入突变的小鼠品系来实现这一目标，以模仿分别在RBM和EDMD中发现的突变。

DESCRIPTION (provided by applicant): Recently, mutations in Four and a half LIM domain 1 (FHL1) gene have been identified in patients with rare forms of myopathies including Reducing Body Myopathy (RBM) and Emery-Dreifuss Muscular Dystrophy (EDMD). Several experimental lines of evidences support the idea that FHL1 plays an important role in skeletal muscle hypertrophy and atrophy. FHL1 is upregulated during embryonic and postnatal skeletal muscle growth and in stretch-induced skeletal muscle hypertrophy. Conversely, FHL1 is downregulated in disuse-induced muscle atrophy. Recently, it was reported that FHL1 overexpression in C2C12 cells enhances myoblast fusion, resulting in hypertrophic myotubes. FHL1 transgenic overexpression in mouse skeletal muscle promotes hypertrophy and stimulates the production of oxidative fiber types. To understand the in vivo role of FHL1, we generated a mouse line in which all isoforms of FHL1 are ubiquitously ablated (FHL1-null mouse). Our preliminary studies on skeletal muscles extracted from FHL1-null mice demonstrate that our model displays a dystrophic phenotype that mimics some physiological and morphological aspects of myopathy as observed in human patients. This confirms the important role that FHL1 plays in muscle growth and homeostasis. However human mutations, which result in different forms of myopathies, are caused by mutations leading to qualitative and quantitative changes, but not a complete loss of FHL1 protein. The overall goal of this proposal is to understand the role that FHL1 plays in skeletal muscle growth and homeostasis and to understand why different mutations in FHL1 result in different myopathies. We will achieve this goal by fully characterizing the phenotype of the currently available FHL1-null mouse line and by creating and detailed characterizing of two more mouse lines in which mutations will be introduced by gene targeting to mimic mutations identified in RBM and EDMD respectively.