Activation of the MEF2 transcription factor in skeletal muscles from myotonic mice

Wu, Hai Yan; Olson, Eric N.

doi:10.1172/jci15417

Cited by 23 publications

(19 citation statements)

References 45 publications

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“…A similar change in fiber type composition can be seen in experimental mice affected with myotonia (29), which is a hallmark of DM1. Elevation of MEF2A in CUGBP1 transgenic mice is consistent with recent data from Dr. Olson's laboratory indicating that MEF2 activity is elevated in slow fibers in mouse muscles with myotonia (29). In these myotonic mice, ϳ80% of fibers are oxidative or slow.…”

Section: Discussionsupporting

confidence: 62%

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Timchenko

Patel

Iakova

et al. 2004

Journal of Biological Chemistry

187

205

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Accumulation of RNA CUG repeats in myotonic dystrophy type 1 (DM1) patients leads to the induction of a CUG-binding protein, CUGBP1, which increases translation of several proteins that are required for myogenesis. In this paper, we examine the role of overexpression of CUGBP1 in DM1 muscle pathology using transgenic mice that overexpress CUGBP1 in skeletal muscle. Our data demonstrate that the elevation of CUGBP1 in skeletal muscle causes overexpression of MEF2A and p21 to levels that are significantly higher than those in skeletal muscle of wild type animals. A similar induction of these proteins is observed in skeletal muscle of DM1 patients with increased levels of CUGBP1. Immunohistological analysis showed that the skeletal muscle from mice overexpressing CUGBP1 is characterized by a developmental delay, muscular dystrophy, and myofiber-type switch: increase of slow/oxidative fibers and the reduction of fast fibers. Examination of molecular mechanisms by which CUGBP1 up-regulates MEF2A shows that CUGBP1 increases translation of MEF2A via direct interaction with GCN repeats located within MEF2A mRNA. Our data suggest that CUGBP1-mediated overexpression of MEF2A and p21 inhibits myogenesis and contributes to the development of muscle deficiency in DM1 patients. DM11 is a multisystem disease mainly characterized by defects in skeletal muscle with the involvement of many tissues and systems such as cardiac muscle, brain, eye, and endocrine system (1). DM1 is caused by an expansion of CTG trinucleotide repeats within the 3Ј-untranslated region of the myotonin protein kinase gene (2). In DM1 patients, the size of DNA CTG expansion correlates with the severity of the disease. Patients with CTG expansion containing 50 -80 CTG repeats are almost asymptomatic. Individuals bearing the myotonin protein kinase gene with 100 -500 CTG repeats develop a disease in adult life (classical adult form of DM1) that is characterized by a progressive muscle wasting with myotonia. The most severe form of DM1, congenital disease, affects patients before or after birth and is associated with long CTG expansions (up to 2,000 repeats). This form of disease is characterized by a delay or arrest of skeletal muscle development (3). Although there is an overlap in range of repeats between different forms of DM1, there is a clear correlation of repeat number with severity of phenotype and reduction of age of onset.Investigations of molecular alterations in DM1 suggest that the expansion of CTG repeats causes the DM1 pathology through different mechanisms, mediated at both DNA and RNA levels. It has been shown that CTG repeats reduce expression of myotonin protein kinase in cis (4), causing abnormalities in cardiac muscle (5). CTG repeats also affect transcription of genes adjacent to myotonin protein kinase (6), leading to the development of cataracts (7,8). A number of recent studies indicate that other symptoms in DM1 such as myotonia (9, 10), delay of skeletal muscle differentiation (11,12), and a resistance to insulin (13) are mediated ...

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Section: Discussionsupporting

confidence: 62%

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Timchenko

Patel

Iakova

et al. 2004

Journal of Biological Chemistry

187

205

View full text Add to dashboard Cite

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“…This could suggest that MEF-2 is DNA bound in the basal state. Furthermore, Wu and Olson (48) found that p38 activation is associated with enhanced MEF-2 transcriptional activity, without changes in MEF-2 DNA-binding activity. Additionally, others imply that MEF-2 DNA binding is a function of the abundance of the MEF-2 protein (7).…”

Section: Discussionmentioning

confidence: 98%

Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle

2004

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Overexpression of GLUT4 in skeletal muscle enhances whole-body insulin action. Exercise increases GLUT4 gene and protein expression, and a binding site for the myocyte enhancer factor 2 (MEF-2) is required on the GLUT4 promoter for this response. However, the molecular mechanisms involved remain elusive. In various cell systems, MEF-2 regulation is a balance between transcriptional repression by histone deacetylases (HDACs) and transcriptional activation by the nuclear factor of activated T-cells (NFAT), peroxisome proliferator-activated receptor-␥ coactivator 1 (PGC-1), and the p38 mitogen-activated protein kinase. The purpose of this study was to determine if these same mechanisms regulate MEF-2 in contracting human skeletal muscle. Seven subjects performed 60 min of cycling at ϳ70% of Vo 2peak . After exercise, HDAC5 was dissociated from MEF-2 and exported from the nucleus, whereas nuclear PGC-1 was associated with MEF-2. Exercise increased total and nuclear p38 phosphorylation and association with MEF-2, without changes in total or nuclear p38 protein abundance. This result was associated with p38 sequence-specific phosphorylation of MEF-2 and an increase in GLUT4 mRNA. Finally, we found no role for NFAT in MEF-2 regulation. From these data, it appears that HDAC5, PGC-1, and p38 regulate MEF-2 and could be potential targets for modulating GLUT4 expression.

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“…Other pathways involve calcium-sensitive proteins including calcineurin, which activates MEF2 by direct dephosphorylation (32) and Ca 2ϩ -calmodulindependent protein kinase, which activates MEF2 by alleviating the repression imposed by the histone deacetylases (HDACs) (51)(52)(53). Signaling via Ca 2ϩ -dependent pathways has recently been proposed as a potential means of fiber-type adaptation because sustained patterns of nerve stimulation elevate intracellular calcium levels (20), and recent experiments in mice support this hypothesis (31,54). Additionally, the transcriptional co-activator PGC-1␣ has been found to elicit slow fiberspecific gene expression, as well as mitochondrial biogenesis, through interaction with MEF2 (30).…”

Section: Discussionmentioning

confidence: 99%

hMusTRD1α1 Represses MEF2 Activation of the Troponin I Slow Enhancer

Polly

Haddadi

Issa

et al. 2003

Journal of Biological Chemistry

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Hardeman, E. C. (1998) Mol. Cell. Biol. 18, 6641-6652) was identified in a yeast one-hybrid screen as a protein that binds within an upstream enhancer-containing region of the skeletal muscle-specific gene, TNNI1 (human troponin I slow; hTnI slow ). It has been proposed that hMus-TRD1␣1 may play an important role in fiber-specific muscle gene expression by virtue of its ability to bind to an Inr-like element (nucleotides ؊977 to ؊960) within the hTnI slow upstream enhancer-containing region that is necessary for slow fiber-specific expression. In this study we demonstrate that both MEF2C, a known regulator of slow fiber-specific genes, and hMusTRD1␣1 regulate hTnI slow through the Inr-like element. Co-transfection assays in C2C12 cells and Cos-7 cells demonstrate that hMusTRD1␣1 represses hTnI slow transcription and prevents MEF2C-mediated activation of hTnI slow transcription. Gel shift analysis shows that hMusTRD1␣1 can abrogate MEF2C binding to its cognate site in the hTnI slow enhancer. Glutathione S-transferase pull-down assays demonstrate that hMusTRD1␣1 can interact with both MEF2C and the nuclear receptor co-repressor. The data support the role of hMusTRD1␣1 as a repressor of slow fiber-specific transcription through mechanisms involving direct interactions with MEF2C and the nuclear receptor co-repressor.

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Activation of the MEF2 transcription factor in skeletal muscles from myotonic mice

Cited by 23 publications

References 45 publications

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle

hMusTRD1α1 Represses MEF2 Activation of the Troponin I Slow Enhancer

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