Expression of CCAAT/Enhancer Binding Protein Beta in Muscle Satellite Cells Inhibits Myogenesis in Cancer Cachexia

Marchildon, François; Lamarche, Émilie; Lala-Tabbert, Neena; St-Louis, Catherine; Wiper‐Bergeron, Nadine

doi:10.1371/journal.pone.0145583

Cited by 33 publications

(44 citation statements)

References 64 publications

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“…Atrogin 1-induced atrophy is mediated by degradation of eIF3f, which suppresses S6K1 activation induced by mTOR as well as MyoD breakdown [78], blocking differentiation and inhibiting myotube formation. These data might partially explain the reduced protein synthesis [74] and impaired muscle regeneration in atrophic muscle during cancer cachexia observed in previous studies [79,80]. Importantly, mice lacking Atrogin 1 [81] and MuRF1 [75] are partially protected from fasting-and denervation-induced muscle wasting, respectively.…”

Section: Dysfunctional Peripheral Handling Of Energy Substratesmentioning

confidence: 57%

Energy metabolism in cachexia

et al. 2019

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Cachexia is a wasting disorder that accompanies many chronic diseases including cancer and results from an imbalance of energy requirements and energy uptake. In cancer cachexia, tumor‐secreted factors and/or tumor–host interactions cause this imbalance, leading to loss of adipose tissue and skeletal and cardiac muscle, which weakens the body. In this review, we discuss how energy enters the body and is utilized by the different organs, including the gut, liver, adipose tissue, and muscle, and how these organs contribute to the energy wasting observed in cachexia. We also discuss futile cycles both between the organs and within the cells, which are often used to fine‐tune energy supply under physiologic conditions. Ultimately, understanding the complex interplay of pathologic energy‐wasting circuits in cachexia can bring us closer to identifying effective treatment strategies for this devastating wasting disease.

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Section: Dysfunctional Peripheral Handling Of Energy Substratesmentioning

confidence: 57%

Energy metabolism in cachexia

et al. 2019

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“…We have previously shown that exposure of myoblasts to conditioned medium from cachexia-inducing tumours, can upregulate C/EBPβ expression and inhibit myogenic differentiation. Indeed, loss of C/EBPβ rescues myoblast differentiation in this model system 28 . Given that ID3 is downstream of C/EBPβ and loss of ID3 expression increases myogenin expression and promotes myogenic differentiation (Fig.…”

Section: Resultsmentioning

confidence: 87%

“…However, in C/EBPβ-overexpressing cells, C/EBPβ recruitment at all Id3 regulatory regions examined was enriched as compared to pLXSN (Fig. 4E ) suggesting that overexpression, which occurs in vivo with sarcopenia and cachexia 28 , 29 , can force C/EBPβ onto elements that are not normally occupied. To confirm specificity, we repeated the ChIP in primary myoblasts isolated from a conditional null mouse where Cebpb is excised in muscle precursor cells ( Cebpb fl/fl Pax7 CreER/wt (C/EBPβ −/− )) (Fig.…”

Section: Resultsmentioning

confidence: 98%

CCAAT/Enhancer Binding Protein β inhibits myogenic differentiation via ID3

AlSudais

Lala-Tabbert

Wiper‐Bergeron

2018

Sci Rep

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Myogenesis is regulated by the coordinated expression of muscle regulatory factors, a family of transcription factors that includes MYOD, MYF5, myogenin and MRF4. Muscle regulatory factors are basic helix-loop-helix transcription factors that heterodimerize with E proteins to bind the regulatory regions of target genes. Their activity can be inhibited by members of the Inhibitor of DNA binding and differentiation (ID) family, which bind E-proteins with high affinity, thereby preventing muscle regulatory factor-dependent transcriptional responses. CCAAT/Enhancer Binding protein beta (C/EBPβ) is a transcription factor expressed in myogenic precursor cells that acts to inhibit myogenic differentiation, though the mechanism remains poorly understood. We identify Id3 as a novel C/EBPβ target gene that inhibits myogenic differentiation. Overexpression of C/EBPβ stimulates Id3 mRNA and protein expression, and is required for C/EBPβ-mediated inhibition of myogenic differentiation. Misexpression of C/EBPβ in myogenic precursors, such as in models of cancer cachexia, prevents the differentiation of myogenic precursors and we show that loss of Id3 rescues differentiation under these conditions, suggesting that the stimulation of Id3 expression by C/EBPβ is an important mechanism by which C/EBPβ inhibits myogenic differentiation.

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“…Recently, over-activation of Notch signaling was shown in progenitor cells in skeletal muscle of dystrophic mice [41]. We have shown that C/EBPβ expression persists in SCs of cachectic muscles and that these cells do not differentiate [42, 43]; thus, it is tempting to hypothesize that C/EBPβ may persist in SCs of dystrophic muscle, upregulating Notch expression and contributing to the dystrophic defect. Our findings provide a mechanism for C/EBPβ-induced cell fate choices in myogenesis and identify C/EBPβ as a novel regulator of Notch signaling.…”

Section: Discussionmentioning

confidence: 99%

CCAAT/enhancer binding protein β is required for satellite cell self-renewal

et al. 2016

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BackgroundPostnatal growth and repair of skeletal muscle relies upon a population of quiescent muscle precursor cells, called satellite cells that can be activated to proliferate and differentiate into new myofibers, as well as self-renew to replenish the satellite cell population. The balance between differentiation and self-renewal is critical to maintain muscle tissue homeostasis, and alterations in this equilibrium can lead to chronic muscle degeneration. The transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is expressed in Pax7+ satellite cells of healthy muscle and is downregulated during myoblast differentiation. Persistent expression of C/EBPβ upregulates Pax7, inhibits MyoD, and blocks myogenic differentiation.MethodsUsing genetic tools to conditionally abrogate C/EBPβ expression in Pax7+ cells, we examined the role of C/EBPβ in self-renewal of satellite cells during muscle regeneration.ResultsWe find that loss of C/EBPβ leads to precocious differentiation at the expense of self-renewal in primary myoblast and myofiber cultures. After a single muscle injury, C/EBPβ-deficient satellite cells fail to self-renew resulting in a reduction of satellite cells available for future rounds of regeneration. After a second round of injury, muscle regeneration is impaired in C/EBPβ conditional knockout mice compared to wild-type control mice. We find that C/EBPβ can regulate Notch2 expression and that restoration of Notch activity in myoblasts lacking C/EBPβ prevents precocious differentiation.ConclusionsThese findings demonstrate that C/EBPβ is a novel regulator of satellite cell self-renewal during muscle regeneration acting at least in part through Notch2.

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Expression of CCAAT/Enhancer Binding Protein Beta in Muscle Satellite Cells Inhibits Myogenesis in Cancer Cachexia

Cited by 33 publications

References 64 publications

Energy metabolism in cachexia

Energy metabolism in cachexia

CCAAT/Enhancer Binding Protein β inhibits myogenic differentiation via ID3

CCAAT/enhancer binding protein β is required for satellite cell self-renewal

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