FHL1 complexes with NFATc1 and GATA2 promoting skeletal muscle hypertrophy during growth but not aging

2017-02-23T04:12:28Z (GMT) by Kane, Jordan Michael
Multiple mutations in the fhl1 gene were identified in several human myopathies (X-linked myopathy with postural muscle atrophy, reducing body myopathy, scapuloperoneal myopathy, Emery-Dreifuss muscular dystrophy and rigid spine syndrome). FHL1 is an adapter protein that scaffolds and regulates transcription complexes as well as regulating the assembly of signaling proteins at the sarcomere (muscle contractile apparatus). FHL1 is expressed most highly in skeletal muscle and its mRNA expression is elevated during perinatal muscle growth. FHL1 levels are also elevated following muscle injury and, conversely, are decreased during muscle wasting. Previously our laboratory has developed transgenic mice overexpressing FHL1 specifically in postnatal skeletal muscle resulting in skeletal muscle hypertrophy. FHL1 binds the transcription factors NFATc1 and GATA2. FHL1 also enhances the transcriptional activity of NFATc1, which is associated with muscle hypertrophy. This study aims to investigate whether FHL1 promotes sustained hypertrophy, and the molecular mechanisms mediating this effect. In this thesis, GATA2 is identified as a direct binding partner of FHL1 in skeletal muscle. FHL1 synergistically activates the transcription of the b3-integrin, MCK and IGF-IR promoters in cooperation with GATA2 and NFATc1. In order to investigate the role of FHL1 in a model of muscle atrophy, muscle from aged FHL1 transgenic mice was evaluated. Wildtype and skeletal-muscle-specific FHL1 transgenic mice at 20 months of age exhibited similar muscle mass, fibre size and regeneration in several major limb muscles from four mice of each genotype (n=4). In contrast, decreased muscle weight, fibre variability and myoblast fusion were evident in FHL1 transgenic gastrocnemius. Although FHL1 complexes with NFATc1 and GATA2 to promote expression of myogenic pathways, this function is likely limited to developmental and/or acute regeneration as the promotion of muscle hypertrophy during post natal growth was not sustained in FHL1 transgenic mice.