title: Identification of FHL1 as a regulator of skeletal muscle mass: implications for human myopathy.
abstract: Regulators of skeletal muscle mass are of interest, given the morbidity and mortality of muscle atrophy and myopathy. Four-and-a-half LIM protein 1 (FHL1) is mutated in several human myopathies, including reducing-body myopathy (RBM). The normal function of FHL1 in muscle and how it causes myopathy remains unknown. We find that FHL1 transgenic expression in mouse skeletal muscle promotes hypertrophy and an oxidative fiber-type switch, leading to increased whole-body strength and fatigue resistance. Additionally, FHL1 overexpression enhances myoblast fusion, resulting in hypertrophic myotubes in C2C12 cells, (a phenotype rescued by calcineurin inhibition). In FHL1-RBM C2C12 cells, there are no hypertrophic myotubes. FHL1 binds with the calcineurin-regulated transcription factor NFATc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1), enhancing NFATc1 transcriptional activity. Mutant RBM-FHL1 forms aggregate bodies in C2C12 cells, sequestering NFATc1 and resulting in reduced NFAT nuclear translocation and transcriptional activity. NFATc1 also colocalizes with mutant FHL1 to reducing bodies in RBM-afflicted skeletal muscle. Therefore, via NFATc1 signaling regulation, FHL1 appears to modulate muscle mass and strength enhancement.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Victoria, Australia.
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Cowling
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McGrath
authors.forename: Mai-Anh
authors.initials: MA
authors.lastname: Nguyen
authors.forename: Denny L
authors.initials: DL
authors.lastname: Cottle
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kee
authors.forename: Susan
authors.initials: S
authors.lastname: Brown
authors.forename: Joachim
authors.initials: J
authors.lastname: Schessl
authors.forename: Yaqun
authors.initials: Y
authors.lastname: Zou
authors.forename: Josephine
authors.initials: J
authors.lastname: Joya
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.forename: Edna C
authors.initials: EC
authors.lastname: Hardeman
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002459:Cell Fusion; D050989:GATA2 Transcription Factor / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D060588:LIM Domain Proteins; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009135:Muscular Diseases / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009929:Organ Size; D011485:Protein Binding; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C101149:FHL1 protein, human; C486306:Fhl1 protein, mouse; D050989:GATA2 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D019703:Calcineurin