The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation

Kivelä, Riikka; Salmela, Ida; Nguyen, Yen; Petrova, Tatiana V.; Koistinen, Heikki A.; Wiener, Zoltán; Alitalo, Kari

doi:10.1038/ncomms13124

Cited by 57 publications

(68 citation statements)

References 48 publications

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“…Yet, several transcription factors not previously associated with lack of mechanical stimuli were also identified. For example, TEF‐1 (TEAD1), a transcription factor implicated in the fast‐to‐slow fiber‐type transition, 37 and PROX1, which is specifically expressed in slow muscle fibers, 38 were downregulated in BR. This was in accordance with the upregulation of genes related to fast‐twitch myosin (see above).…”

Section: Resultsmentioning

confidence: 99%

“…Our data add Prox1 as a factor involved in the unloading‐induced fiber shifting. Prox1, which was downregulated after 84‐day of bed rest, is specifically expressed in slow muscle fibers 38 . This factor is an important component of the molecular program protecting the slow fiber type and activates the NFAT pathway (a key regulator of slow muscle fiber phenotype) 38 .…”

Section: Discussionmentioning

confidence: 99%

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Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures

et al. 2020

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This study explored the muscle genome‐wide response to long‐term unloading (84‐day bed rest) in 21 men. We hypothesized that a part of the bed rest‐induced gene expression signature would be resilient to a concurrent flywheel resistance exercise (RE) countermeasure. Using DNA microarray technology analyzing 35 345 gene‐level probe‐sets, we identified 335 annotated probe‐sets that were downregulated, and 315 that were upregulated after bed rest (P < .01). Besides a predictable differential expression of genes and pathways related to mitochondria (downregulation; false‐discovery rates (FDR) <1E‐04), ubiquitin system (upregulation; FDR = 3E‐02), and skeletal muscle energy metabolism and structure (downregulation; FDR ≤ 3E‐03), 84‐day bed rest also altered circadian rhythm regulation (upregulation; FDR = 3E‐02). While most of the bed rest‐induced changes were counteracted by RE, 209 transcripts were resilient to the exercise countermeasure. Genes upregulated after bed rest were particularly resistant to training (P < .001 vs downregulated, non‐reversed genes). Specifically, “Translation Factors,” “Proteasome Degradation,” “Cell Cycle,” and “Nucleotide Metabolism” pathways were not normalized by RE. This study provides an unbiased high‐throughput transcriptomic signature of one of the longest unloading periods in humans to date. Classical disuse‐related changes in structural and metabolic genes/pathways were identified, together with a novel upregulation of circadian rhythm transcripts. In the context of previous bed rest campaigns, the latter seemed to be related to the duration of unloading, suggesting the transcriptomic machinery continues to adapt throughout extended disuse periods. Despite that the RE training offset most of the bed rest‐induced muscle‐phenotypic and transcriptomic alterations, we contend that the human skeletal muscle also displays a residual transcriptomic signature of unloading that is resistant to an established exercise countermeasure.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures

et al. 2020

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“…During myoblast differentiation, PROX1 expression increases and it regulates the expression of other myogenic factors and components of the muscle contractile machinery (Kivela et al, 2016). In experimental RMS models, myogenic regulatory factors are expressed in the tumors regardless of their cells of origin (Tenente et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous work has shown that the prospero-related homeobox 1 (PROX1) factor is expressed in muscle stem cells, and that it is essential for myoblast differentiation and slow muscle fiber type characteristics (Kivela et al, 2016). PROX1 is highly conserved among vertebrates and it is essential for lymphatic endothelial cell differentiation and for the development of eye, liver and heart (Elsir et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

PROX1 transcription factor is a master regulator of myogenic and oncogenic features of rhabdomyosarcoma

Gizaw

Kallio

Punger

et al. 2020

Preprint

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1 2 Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue cancer in need for novel 3 therapies. Here we show that the PROX1 transcription factor, which is essential for normal 4 myoblast differentiation, is highly expressed in RMS tumors. We demonstrate that PROX1 5 is needed for RMS cell stemness and growth in vitro, and for RMS tumor formation in mouse 6 xenograft models. In addition, we unveil that PROX1 is an essential for myogenic properties 7 in RMS. PROX1 depletion reprogrammed the RMS transcriptome to resemble benign 8 mesenchymal stem cells and repressed many of the previously identified RMS effector 9 transcripts and myogenic genes. By using proximity labeling and mass spectrometry, we 10 found that PROX1 interacts with the NuRD and CoREST complexes containing class I 11HDACs. Our studies reveal a major role of PROX1-HDAC interaction in RMS and give 12 insights that inhibiting this interaction could be a promising therapeutic approach. 13 14

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“…At this early phase, well‐documented PGC1α/PPARδ systems and a motor nerve/calcium‐ion signaling pathway are unlikely to contribute to the slow‐fiber commitment. This consideration is based on findings that the expression of PPARδ, PGC1α and its target genes (PDK4 and UCP3) and CaMKIV, CnA, nuclear factor of activated T‐cells, cytoplasmic 1 (NFATC1), regulator of CnA 1 (RCAN1), and prospero‐related homeobox 1 (Prox1) were all unaffected by Sema3A deletion in satellite cell cultures prepared from control and Sema3A‐cKO mice (Fig. C, assayed at 72 hours post‐differentiation by RT‐qPCR).…”

Section: Discussionmentioning

confidence: 99%

Slow-Myofiber Commitment by Semaphorin 3A Secreted from Myogenic Stem Cells

Tatsumi¹,

Suzuki

Q.³

et al. 2017

Stem Cells

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Recently, we found that resident myogenic stem satellite cells upregulate a multi-functional secreted protein, semaphorin 3A (Sema3A), exclusively at the early-differentiation phase in response to muscle injury; however, its physiological significance is still unknown. Here we show that Sema3A impacts slow-twitch fiber generation through a signaling pathway, cell-membrane receptor (neuropilin2-plexinA3) → myogenin-myocyte enhancer factor 2D → slow myosin heavy chain. This novel axis was found by small interfering RNA-transfection experiments in myoblast cultures, which also revealed an additional element that Sema3A-neuropilin1/plexinA1, A2 may enhance slow-fiber formation by activating signals that inhibit fast-myosin expression. Importantly, satellite cell-specific Sema3A conditional-knockout adult mice (Pax7CreER -Sema3A ° activated by tamoxifen-i.p. injection) provided direct in vivo evidence for the Sema3A-driven program, by showing that slow-fiber generation and muscle endurance were diminished after repair from cardiotoxin-injury of gastrocnemius muscle. Overall, the findings highlight an active role for satellite cell-secreted Sema3A ligand as a key "commitment factor" for the slow-fiber population during muscle regeneration. Results extend our understanding of the myogenic stem-cell strategy that regulates fiber-type differentiation and is responsible for skeletal muscle contractility, energy metabolism, fatigue resistance, and its susceptibility to aging and disease. Stem Cells 2017;35:1815-1834.

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The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation

Cited by 57 publications

References 48 publications

Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures

Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures

PROX1 transcription factor is a master regulator of myogenic and oncogenic features of rhabdomyosarcoma

Slow-Myofiber Commitment by Semaphorin 3A Secreted from Myogenic Stem Cells

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