A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis

O’Connor, Roddy S.; Mills, Stephen T.; Jones, Kristen A.; Ho, Steffan N.; Pavlath, Grace K.

doi:10.1242/jcs.03307

Cited by 111 publications

(105 citation statements)

References 81 publications

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“…14 Of the three NFAT5 targets involved in osmolyte accumulation we tested for this study, we found only AR to be present in substantial amounts in normal muscle, which confirms an earlier report 14 and points to a physiological role in muscle homeostasis. 15 Levels of TauT (The Human Protein Atlas: http://www.proteinatlas.…”

Section: Discussionsupporting

confidence: 81%

“…The relationship between NFAT5 and immune cell function has been put forward, and in macrophages, myo-inositol is believed to have a central role in cell volume regulation during phagocytosis. Infiltrating immune cells in murine muscle subjected to experimental muscle injury express NFAT5, 14 and SMIT protein levels have been shown to increase in liver macrophages subjected to hypertonic conditions. 40…”

Section: Smit Is Expressed In Muscle-infiltrating Immune Cellsmentioning

confidence: 99%

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Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Paepe

Martin

Herbelet

et al. 2016

Laboratory Investigation

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Alongside well-known nuclear factor κB (NFκB) and its associated cytokine networks, nuclear factor of activated T cells 5 (NFAT5), the master regulator of cellular osmoprotective programs, comes forward as an inflammatory regulator. To gain insight into its yet unexplored role in muscle disease, we studied the expression of NFAT5 target proteins involved in osmolyte accumulation: aldose reductase (AR), taurine transporter (TauT), and sodium myo-inositol co-transporter (SMIT). We analyzed idiopathic inflammatory myopathy and Duchenne muscular dystrophy muscle biopsies and myotubes in culture, using immunohistochemistry, immunofluorescence, and western blotting. We report that the level of constitutive AR was upregulated in patients, most strongly so in Duchenne muscular dystrophy. TauT and SMIT expression levels were induced in patients' muscle fibers, mostly representing regenerating and atrophic fibers. In dermatomyositis, strong staining for AR, TauT, and SMIT in atrophic perifascicular fibers was accompanied by staining for other molecular NFAT5 targets, including chaperones, chemokines, and inducible nitric oxide synthase. In these fibers, NFAT5 and NFκB p65 staining coincided, linking both transcription factors with this important pathogenic hallmark. In sporadic inclusion body myositis, SMIT localized to inclusions inside muscle fibers. In addition, SMIT was expressed by a substantial subset of muscle-infiltrating macrophages and T cells in patient biopsies. Our results indicate that osmolyte pathways may contribute to normal muscle functioning, and that activation of AR, TauT, and SMIT in muscle inflammation possibly contributes to the tissue's failing program of damage control.

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Section: Discussionsupporting

confidence: 81%

Section: Smit Is Expressed In Muscle-infiltrating Immune Cellsmentioning

confidence: 99%

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Paepe

Martin

Herbelet

et al. 2016

Laboratory Investigation

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“…Indeed, it has been shown that NFAT5 is a transcriptional factor that stimulates cell migration (Jauliac et al, 2002;O'Connor et al, 2007). As expected, NFAT5 over-expression in MDA-MB-231 cells increased cell migration (Figure 2a), whereas NFAT5 depletion decreased it (Figure 2b).…”

Section: Resultssupporting

confidence: 71%

“…It will be interesting to test whether this ddx5/ddx17-dependent mechanism is involved in NFAT5 protein level regulation in hyperosmotic conditions. Similarly, NFAT5 protein level is regulated during development and NFAT5 has a role in muscle differentiation (O'Connor et al, 2007). As ddx5 and ddx17 also have a role in muscle differentiation (Caretti et al, 2006), it will be interesting to test the interplay between NFAT5 and ddx5/ddx17 in muscle development.…”

Section: Discussionmentioning

confidence: 99%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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“…Five NFAT isoforms have been identified (16), and four isoforms (NFATc1, -c2, -c3, and -5) are expressed in skeletal muscle (17,18). NFATc1, -c2, -c3, and -5 have overlapping but also nonredundant functions in skeletal muscle, including control of myogenic differentiation, myoblast migration and fusion, and fiber type specification (18 -21).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase 3β Suppresses Myogenic Differentiation through Negative Regulation of NFATc3

Velden

Schols

Willems

et al. 2008

Journal of Biological Chemistry

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Skeletal muscle atrophy is a prominent and disabling feature in many chronic diseases. Prevention or reversal of muscle atrophy by stimulation of skeletal muscle growth could be an important therapeutic strategy. Glycogen synthase kinase 3␤ (GSK-3␤) has been implicated in the negative regulation of skeletal muscle growth. Since myogenic differentiation is an essential part of muscle growth, we investigated if inhibition of GSK-3␤ is sufficient to stimulate myogenic differentiation and whether this depended on regulation of the transcription factor nuclear factor of activated T-cells (NFAT). In both myogenically converted mouse embryonic fibroblasts and C2C12 myoblasts, deficiency of GSK-3␤ protein (activity) resulted in enhanced myotube formation and muscle-specific gene expression during differentiation, which was reversed by reintroduction of wild type but not kinase-inactive (K85R) GSK-3␤. In addition, GSK-3␤ inhibition restored myogenic differentiation following calcineurin blockade, which suggested the involvement of NFAT. GSK-3␤-deficient mouse embryonic fibroblasts or myoblasts displayed enhanced nuclear translocation of NFATc3 and elevated NFAT-sensitive promoter transactivation, which was reduced by reintroducing wild type, but not K85R GSK-3␤. Overexpression of NFATc3 increased muscle gene promoter transactivation, which was abolished by co-expression of wild type GSK-3␤. Finally, stimulation of muscle gene expression observed following GSK-3␤ inhibition was strongly attenuated in NFATc3-deficient myoblasts, indicating that this response requires NFATc3. Collectively, our data demonstrate negative regulation of myogenic differentiation by GSK-3␤ through a transcriptional mechanism that depends on NFATc3. Inhibition of GSK-3␤ may be a potential strategy in prevention or treatment of muscle atrophy.Maintenance of muscle mass is critical for health, and loss of skeletal muscle mass compromises human physical condition and survival in chronic diseases, such as chronic obstructive pulmonary disease (1, 2). Restoring lost muscle mass is important for improving quality of life and ultimately disease prognosis (3). To restore muscle mass and improve muscle function in various diseases conditions, a better understanding of the molecular mechanisms of skeletal muscle (re)growth is required. Skeletal muscle differentiation is a critical element of certain types of postnatal growth of the skeletal musculature and is mainly dependent on satellite cells (quiescent myoblasts), which upon activation proliferate, differentiate, and fuse with existing muscle fibers or with each other to form new myofibers (4). Myoblast fusion allows additional muscle growth by myonuclear accretion, beyond the limitations imposed by the myonuclear domain (i.e. the maximal cytoplasm/nucleus ratio) (5).The protein kinase GSK-3 2 is ubiquitously expressed, and, although it was originally identified as a suppressor of glycogen synthase (6), GSK-3 has been implicated in a myriad of metabolic and signaling pathways (7). Recent studies have ide...

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A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis

Cited by 111 publications

References 81 publications

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Glycogen Synthase Kinase 3β Suppresses Myogenic Differentiation through Negative Regulation of NFATc3

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