Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling

Dee, K; Freer, M; Mei, Yuxia; Weyman, Crystal M.

doi:10.1038/sj.cdd.4400930

Cited by 49 publications

(45 citation statements)

References 39 publications

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“…Caspase 3 and caspase 7 activity generally increased over time, as expected (Dee et al, 2002). However, further increased caspase activity was measured at 36 and 38 h post transduction in myoblasts expressing DUX4, and in those expressing tMALDUX4–VP16 at 38 h (Fig.…”

Section: Resultssupporting

confidence: 80%

DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

Knopp

Krom

Banerji³

et al. 2016

Journal of Cell Science

107

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Skeletal muscle wasting in facioscapulohumeral muscular dystrophy (FSHD) results in substantial morbidity. On a disease-permissive chromosome 4qA haplotype, genomic and/or epigenetic changes at the D4Z4 macrosatellite repeat allows transcription of the DUX4 retrogene. Analysing transgenic mice carrying a human D4Z4 genomic locus from an FSHD-affected individual showed that DUX4 was transiently induced in myoblasts during skeletal muscle regeneration. Centromeric to the D4Z4 repeats is an inverted D4Z4 unit encoding DUX4c. Expression of DUX4, DUX4c and DUX4 constructs, including constitutively active, dominant-negative and truncated versions, revealed that DUX4 activates target genes to inhibit proliferation and differentiation of satellite cells, but that it also downregulates target genes to suppress myogenic differentiation. These transcriptional changes elicited by DUX4 in mouse have significant overlap with genes regulated by DUX4 in man. Comparison of DUX4 and DUX4c transcriptional perturbations revealed that DUX4 regulates genes involved in cell proliferation, whereas DUX4c regulates genes engaged in angiogenesis and muscle development, with both DUX4 and DUX4c modifing genes involved in urogenital development. Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state.

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Section: Resultssupporting

confidence: 80%

DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

Knopp

Krom

Banerji³

et al. 2016

Journal of Cell Science

107

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“…The growth of 10T1/2 fibroblasts and ER-MyoD:10T1/2 fibroblasts, as well as the growth and differentiation properties 23A2 myoblasts and 23A2 myoblasts silenced for MyoD expression, have been reported previously [11, 16, 21]. …”

Section: Methodsmentioning

confidence: 73%

“…We have previously reported that differentiation and apoptosis in response to culture in differentiation media (DM) are separable events in skeletal myoblasts, thus indicating the requirement for distinct signaling molecules [11]. We further determined that increased expression of the pro-apoptotic Bcl 2 family member PUMA was required for, and distinct to, the process of apoptosis in skeletal myoblasts [15].…”

Section: Introductionmentioning

confidence: 99%

“…We further determined that increased expression of the pro-apoptotic Bcl 2 family member PUMA was required for, and distinct to, the process of apoptosis in skeletal myoblasts [15]. In contrast to later signaling events which are evidently unique to either apoptosis or differentiation, initial signaling events will have a commonality in that both differentiation and apoptosis are induced by culture in DM and abrogated by signaling events such as those initiated by oncogenic Ras [9, 11,12]. To this point, we have reported that shRNAi-mediated silencing of the muscle regulatory transcription factor MyoD in myoblasts abrogated apoptosis, as well as differentiation, in response to culture in DM.…”

Section: Introductionmentioning

confidence: 99%

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The muscle regulatory transcription factor MyoD participates with p53 to directly increase the expression of the pro-apoptotic Bcl2 family member PUMA

et al. 2017

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The muscle regulatory transcription factor MyoD is a master regulator of skeletal myoblast differentiation. We have previously reported that MyoD is also necessary for the elevated expression of the pro-apoptotic Bcl2 family member PUMA, and the ensuing apoptosis, that occurs in a subset of myoblasts induced to differentiate. Herein, we report the identification of a functional MyoD binding site within the extended PUMA promoter. In silico analysis of the murine PUMA extended promoter revealed three potential MyoD binding sites within 2kb of the transcription start site. Expression from a luciferase reporter construct containing this 2kb fragment was enhanced by activation of MyoD in both myoblasts and fibroblasts and diminished by silencing of MyoD in myoblasts. Experiments utilizing truncated versions of this promoter region revealed that the potential binding site at position −857 was necessary for expression. Chromatin immunoprecipitation (ChIP) analysis confirmed binding of MyoD to the DNA region encompassing position −857. The increase in MyoD binding to the PUMA promoter as a consequence of culture in differentiation media (DM) was comparable to the increase in MyoD binding at the myogenin promoter and was diminished in myoblasts silenced for MyoD expression. Finally, ChIP analysis using an antibody specific for the transcription factor p53 demonstrated that, in myoblasts silenced for MyoD expression, p53 binding to the PUMA promoter was diminished in response to culture in DM. These data indicate that MyoD plays a direct role in regulating PUMA expression and reveal functional consequences of MyoD expression on p53 mediated transcription of PUMA.

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“…These Pax7 + /MyoD - cells are thought to maintain a small pool of muscle stem cells, from which future proliferative myoblasts may be derived. Cells that escape differentiation and that fail to return to quiescence undergo apoptosis [5,6]. Indeed, apoptosis is normally regarded as a natural part of differentiation, and identifying factors involved in cell cycle control and survival undoubtedly play an important role in our general understanding of myogenesis and in the etiology of many muscle degenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Dual Oxidase Maturation factor 1 (DUOXA1) overexpression increases reactive oxygen species production and inhibits murine muscle satellite cell differentiation

Sandiford¹,

Kennedy

Xie

et al. 2014

Cell Commun Signal

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BackgroundDual oxidase maturation factor 1 (DUOXA1) has been associated with the maturation of the reactive oxygen species (ROS) producing enzyme, dual oxidase 1 (DUOX1) in the adult thyroid. However, ROS have also been implicated in the development of several tissues. We found that activated muscle satellite cells and primary myoblasts isolated from mice express robust levels of DUOXA1 and that its levels are altered as cells differentiate.ResultsTo determine whether DUOXA1 levels affect muscle differentiation, we used an adenoviral construct (pCMV5-DUOXA1-GFP) to drive constitutive overexpression of this protein in primary myoblasts. High levels of DUOXA1 throughout myogenesis resulted in enhanced H2O2 production, fusion defects, reduced expression of early (myogenin) and late (myosin heavy chain) markers of differentiation, and elevated levels of apoptosis compared to control cells infected with an empty adenoviral vector (pCMV5-GFP). DUOXA1 knockdown (using a DUOXA1 shRNA construct) resulted in enhanced differentiation compared to cells subjected to a control shRNA, and subjecting DUOXA1 overexpressing cells to siRNAs targeting DUOX1 or apoptosis signal-regulating kinase 1 (ASK1) rescued the phenotype.ConclusionsThis study represents the first to demonstrate the importance of DUOXA1 in skeletal muscle myoblasts and that DUOXA1 overexpression in muscle stem cells induces apoptosis and inhibits differentiation through DUOX1 and ASK1.

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Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling

Cited by 49 publications

References 39 publications

DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

The muscle regulatory transcription factor MyoD participates with p53 to directly increase the expression of the pro-apoptotic Bcl2 family member PUMA

Dual Oxidase Maturation factor 1 (DUOXA1) overexpression increases reactive oxygen species production and inhibits murine muscle satellite cell differentiation

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