Dlk1 is necessary for proper skeletal muscle development and regeneration.
Delta-like 1homolog (Dlk1) is an imprinted gene encoding a transmembrane protein whose increased expression has been associated with muscle hypertrophy in animal models. However, the mechanisms by which Dlk1 regulates skeletal muscle plasticity remain unknown. Here we combine conditional gene knocko...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-11-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015055&type=printable |
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| author | Jolena N Waddell Peijing Zhang Yefei Wen Sanjay K Gupta Aleksey Yevtodiyenko Jennifer V Schmidt Christopher A Bidwell Ashok Kumar Shihuan Kuang |
| author_facet | Jolena N Waddell Peijing Zhang Yefei Wen Sanjay K Gupta Aleksey Yevtodiyenko Jennifer V Schmidt Christopher A Bidwell Ashok Kumar Shihuan Kuang |
| author_sort | Jolena N Waddell |
| collection | DOAJ |
| description | Delta-like 1homolog (Dlk1) is an imprinted gene encoding a transmembrane protein whose increased expression has been associated with muscle hypertrophy in animal models. However, the mechanisms by which Dlk1 regulates skeletal muscle plasticity remain unknown. Here we combine conditional gene knockout and over-expression analyses to investigate the role of Dlk1 in mouse muscle development, regeneration and myogenic stem cells (satellite cells). Genetic ablation of Dlk1 in the myogenic lineage resulted in reduced body weight and skeletal muscle mass due to reductions in myofiber numbers and myosin heavy chain IIB gene expression. In addition, muscle-specific Dlk1 ablation led to postnatal growth retardation and impaired muscle regeneration, associated with augmented myogenic inhibitory signaling mediated by NF-κB and inflammatory cytokines. To examine the role of Dlk1 in satellite cells, we analyzed the proliferation, self-renewal and differentiation of satellite cells cultured on their native host myofibers. We showed that ablation of Dlk1 inhibits the expression of the myogenic regulatory transcription factor MyoD, and facilitated the self-renewal of activated satellite cells. Conversely, Dlk1 over-expression inhibited the proliferation and enhanced differentiation of cultured myoblasts. As Dlk1 is expressed at low levels in satellite cells but its expression rapidly increases upon myogenic differentiation in vitro and in regenerating muscles in vivo, our results suggest a model in which Dlk1 expressed by nascent or regenerating myofibers non-cell autonomously promotes the differentiation of their neighbor satellite cells and therefore leads to muscle hypertrophy. |
| format | Article |
| id | doaj-art-aa0cdc7fe65544d0bb7e67c03791d396 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2010-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-aa0cdc7fe65544d0bb7e67c03791d3962025-08-20T03:19:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-11-01511e1505510.1371/journal.pone.0015055Dlk1 is necessary for proper skeletal muscle development and regeneration.Jolena N WaddellPeijing ZhangYefei WenSanjay K GuptaAleksey YevtodiyenkoJennifer V SchmidtChristopher A BidwellAshok KumarShihuan KuangDelta-like 1homolog (Dlk1) is an imprinted gene encoding a transmembrane protein whose increased expression has been associated with muscle hypertrophy in animal models. However, the mechanisms by which Dlk1 regulates skeletal muscle plasticity remain unknown. Here we combine conditional gene knockout and over-expression analyses to investigate the role of Dlk1 in mouse muscle development, regeneration and myogenic stem cells (satellite cells). Genetic ablation of Dlk1 in the myogenic lineage resulted in reduced body weight and skeletal muscle mass due to reductions in myofiber numbers and myosin heavy chain IIB gene expression. In addition, muscle-specific Dlk1 ablation led to postnatal growth retardation and impaired muscle regeneration, associated with augmented myogenic inhibitory signaling mediated by NF-κB and inflammatory cytokines. To examine the role of Dlk1 in satellite cells, we analyzed the proliferation, self-renewal and differentiation of satellite cells cultured on their native host myofibers. We showed that ablation of Dlk1 inhibits the expression of the myogenic regulatory transcription factor MyoD, and facilitated the self-renewal of activated satellite cells. Conversely, Dlk1 over-expression inhibited the proliferation and enhanced differentiation of cultured myoblasts. As Dlk1 is expressed at low levels in satellite cells but its expression rapidly increases upon myogenic differentiation in vitro and in regenerating muscles in vivo, our results suggest a model in which Dlk1 expressed by nascent or regenerating myofibers non-cell autonomously promotes the differentiation of their neighbor satellite cells and therefore leads to muscle hypertrophy.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015055&type=printable |
| spellingShingle | Jolena N Waddell Peijing Zhang Yefei Wen Sanjay K Gupta Aleksey Yevtodiyenko Jennifer V Schmidt Christopher A Bidwell Ashok Kumar Shihuan Kuang Dlk1 is necessary for proper skeletal muscle development and regeneration. PLoS ONE |
| title | Dlk1 is necessary for proper skeletal muscle development and regeneration. |
| title_full | Dlk1 is necessary for proper skeletal muscle development and regeneration. |
| title_fullStr | Dlk1 is necessary for proper skeletal muscle development and regeneration. |
| title_full_unstemmed | Dlk1 is necessary for proper skeletal muscle development and regeneration. |
| title_short | Dlk1 is necessary for proper skeletal muscle development and regeneration. |
| title_sort | dlk1 is necessary for proper skeletal muscle development and regeneration |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015055&type=printable |
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