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

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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.