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

Cowling BS, McGrath MJ, Nguyen MA, Cottle DL, Kee AJ, Brown S, Schessl J, Zou Y, Joya J, Bönnemann CG, Hardeman EC, Mitchell CA - J. Cell Biol. (2008)

Bottom Line: In FHL1-RBM C2C12 cells, there are no hypertrophic myotubes.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Victoria, Australia.

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.

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FHL1 regulates NFAT-mediated signaling in skeletal muscle. Wild-type FHL1 complexes with NFATc1 to increase its transcriptional activity, promoting skeletal muscle hypertrophy and oxidative fiber type expression. FHL1-RBM mutations sequester NFATc1 into reducing body aggregates, resulting in its reduced nuclear translocation and reduced activation of gene transcription.
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fig8: FHL1 regulates NFAT-mediated signaling in skeletal muscle. Wild-type FHL1 complexes with NFATc1 to increase its transcriptional activity, promoting skeletal muscle hypertrophy and oxidative fiber type expression. FHL1-RBM mutations sequester NFATc1 into reducing body aggregates, resulting in its reduced nuclear translocation and reduced activation of gene transcription.

Mentions: FHL1 has recently been identified as the gene mutated in several familial and sporadic human myopathies (Quinzii et al., 2008; Schessl et al., 2008; Windpassinger et al., 2008). However, the normal function of FHL1 in skeletal muscle and its molecular targets are largely uncharacterized. The discovery that FHL1 expression increases muscle fiber size and oxidative slow fiber type expression, leading to increased muscle strength and endurance, identifies it as a regulator of skeletal muscle mass. FHL1 complexes with NFATc1, thereby enhancing its transcriptional activity. In contrast, mutant FHL1 proteins that cause RBM sequestered NFATc1 to reducing body aggregates, resulting in decreased NFATc1 nuclear translocation and transcriptional activity. Collectively, the data presented here provide evidence for a role for FHL1 in regulating skeletal muscle mass via regulation of NFATc1 transcriptional activity (Fig. 8).


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

Cowling BS, McGrath MJ, Nguyen MA, Cottle DL, Kee AJ, Brown S, Schessl J, Zou Y, Joya J, Bönnemann CG, Hardeman EC, Mitchell CA - J. Cell Biol. (2008)

FHL1 regulates NFAT-mediated signaling in skeletal muscle. Wild-type FHL1 complexes with NFATc1 to increase its transcriptional activity, promoting skeletal muscle hypertrophy and oxidative fiber type expression. FHL1-RBM mutations sequester NFATc1 into reducing body aggregates, resulting in its reduced nuclear translocation and reduced activation of gene transcription.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2600747&req=5

fig8: FHL1 regulates NFAT-mediated signaling in skeletal muscle. Wild-type FHL1 complexes with NFATc1 to increase its transcriptional activity, promoting skeletal muscle hypertrophy and oxidative fiber type expression. FHL1-RBM mutations sequester NFATc1 into reducing body aggregates, resulting in its reduced nuclear translocation and reduced activation of gene transcription.
Mentions: FHL1 has recently been identified as the gene mutated in several familial and sporadic human myopathies (Quinzii et al., 2008; Schessl et al., 2008; Windpassinger et al., 2008). However, the normal function of FHL1 in skeletal muscle and its molecular targets are largely uncharacterized. The discovery that FHL1 expression increases muscle fiber size and oxidative slow fiber type expression, leading to increased muscle strength and endurance, identifies it as a regulator of skeletal muscle mass. FHL1 complexes with NFATc1, thereby enhancing its transcriptional activity. In contrast, mutant FHL1 proteins that cause RBM sequestered NFATc1 to reducing body aggregates, resulting in decreased NFATc1 nuclear translocation and transcriptional activity. Collectively, the data presented here provide evidence for a role for FHL1 in regulating skeletal muscle mass via regulation of NFATc1 transcriptional activity (Fig. 8).

Bottom Line: In FHL1-RBM C2C12 cells, there are no hypertrophic myotubes.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Victoria, Australia.

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.

Show MeSH
Related in: MedlinePlus