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

描述（由申请人提供）：最近，在罕见形式的肌病患者中发现了4.5 LIM结构域1 （FHL1）基因突变，包括减少体肌病（RBM）和emry - dreifuss肌营养不良（EDMD）。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和拉伸诱导的骨骼肌肥大过程中上调。相反，FHL1在废用性肌肉萎缩中下调。最近有报道称，FHL1在C2C12细胞中过表达可增强成肌细胞融合，导致肌管肥厚。FHL1基因在小鼠骨骼肌中的过表达促进了骨骼肌的肥大，并刺激了氧化纤维类型的产生。为了了解FHL1在体内的作用，我们产生了一个小鼠系，在这个小鼠系中，所有的FHL1亚型都被普遍切除（FHL1-null小鼠）。我们对从fh1缺失小鼠中提取的骨骼肌的初步研究表明，我们的模型显示出营养不良表型，模仿了在人类患者中观察到的肌病的一些生理和形态学方面。这证实了FHL1在肌肉生长和体内平衡中的重要作用。然而，导致不同形式肌病的人类突变是由导致定性和定量变化的突变引起的，而不是FHL1蛋白的完全丧失。本提案的总体目标是了解FHL1在骨骼肌生长和体内平衡中的作用，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fh1 -null小鼠系的表型，并通过创建和详细表征另外两个小鼠系，其中将通过基因靶向引入突变来模拟分别在RBM和EDMD中发现的突变，从而实现这一目标。

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. PUBLIC HEALTH RELEVANCE: Mutations in FHL1 cause a number of rare forms of myopathy. Results of the proposed studies will improve our understanding of the diseases caused by FHL1 mutations and more generally, pathways operating in myopathy. In addition, resulting mouse lines will be invaluable as test models for potential therapies.