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Published online
doi:10.1083/jcb.200804077
The Journal of Cell Biology, Vol. 183, No. 6, 1033-1048
The Rockefeller University Press, 0021-9525 $30.00
© Cowling et al.
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Article

Identification of FHL1 as a regulator of skeletal muscle mass: implications for human myopathy



Belinda S. Cowling1, Meagan J. McGrath1, Mai-Anh Nguyen3, Denny L. Cottle1, Anthony J. Kee3,4, Susan Brown1, Joachim Schessl2, Yaqun Zou2, Josephine Joya3, Carsten G. Bönnemann2, Edna C. Hardeman3,4, and Christina A. Mitchell1

1 Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Victoria, Australia
2 Division of Neurology, the Children's Hospital of Philadelphia, Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
3 Muscle Development Unit, the Children's Medical Research Institute, Westmead, Sydney 2145, New South Wales, Australia
4 School of Medical Sciences, the University of New South Wales, Sydney 2052, New South Wales, Australia

Correspondence to Christina A. Mitchell: christina.mitchell{at}med.monash.edu.au

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.

Abbreviations used in this paper: CsA, cyclosporine A; CSA, cross-sectional area; EDL, extensor digitorum longus; FDP, flexor digitorum profundus; FHL, four-and-a-half LIM protein; HSA, human skeletal muscle {alpha}-actin; LIM, Lin-11, Isl-1, Mec-3; MHC, myosin heavy chain; NBT, nitro blue tetrazolium chloride; NFAT, nuclear factor of activated T cells; RBM, reducing body myopathy.

© 2008 Cowling et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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