Runx1 Transcription Factor Is Required for Myoblasts Proliferation during Muscle Regeneration

PLoS Genet. 2015 Aug 14;11(8):e1005457. doi: 10.1371/journal.pgen.1005457. eCollection 2015 Aug.

Abstract

Following myonecrosis, muscle satellite cells proliferate, differentiate and fuse, creating new myofibers. The Runx1 transcription factor is not expressed in naïve developing muscle or in adult muscle tissue. However, it is highly expressed in muscles exposed to myopathic damage yet, the role of Runx1 in muscle regeneration is completely unknown. Our study of Runx1 function in the muscle's response to myonecrosis reveals that this transcription factor is activated and cooperates with the MyoD and AP-1/c-Jun transcription factors to drive the transcription program of muscle regeneration. Mice lacking dystrophin and muscle Runx1 (mdx-/Runx1f/f), exhibit impaired muscle regeneration leading to age-dependent muscle waste, gradual decrease in motor capabilities and a shortened lifespan. Runx1-deficient primary myoblasts are arrested at cell cycle G1 and consequently differentiate. Such premature differentiation disrupts the myoblasts' normal proliferation/differentiation balance, reduces the number and size of regenerating myofibers and impairs muscle regeneration. Our combined Runx1-dependent gene expression, ChIP-seq, ATAC-seq and histone H3K4me1/H3K27ac modification analyses revealed a subset of Runx1-regulated genes that are co-occupied by MyoD and c-Jun in mdx-/Runx1f/f muscle. The data provide unique insights into the transcriptional program driving muscle regeneration and implicate Runx1 as an important participant in the pathology of muscle wasting diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Consensus Sequence
  • Core Binding Factor Alpha 2 Subunit / physiology*
  • Female
  • Gene Expression
  • Gene Expression Regulation
  • Genes, jun
  • Male
  • Mice, Inbred mdx
  • Muscle, Skeletal / physiology*
  • MyoD Protein / metabolism
  • Myoblasts / physiology*
  • Regeneration*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Runx1 protein, mouse

Grant support

This work was supported by the Israel Science Foundation (grant number 743/11, URL: www.isf.org.il). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.