PITX2 Enhances the Regenerative Potential of Dystrophic Skeletal Muscle Stem Cells

Stem Cell Reports. 2018 Apr 10;10(4):1398-1411. doi: 10.1016/j.stemcr.2018.03.009.

Abstract

Duchenne muscular dystrophy (DMD), one of the most lethal genetic disorders, involves progressive muscle degeneration resulting from the absence of DYSTROPHIN. Lack of DYSTROPHIN expression in DMD has critical consequences in muscle satellite stem cells including a reduced capacity to generate myogenic precursors. Here, we demonstrate that the c-isoform of PITX2 transcription factor modifies the myogenic potential of dystrophic-deficient satellite cells. We further show that PITX2c enhances the regenerative capability of mouse DYSTROPHIN-deficient satellite cells by increasing cell proliferation and the number of myogenic committed cells, but importantly also increasing dystrophin-positive (revertant) myofibers by regulating miR-31. These PITX2-mediated effects finally lead to improved muscle function in dystrophic (DMD/mdx) mice. Our studies reveal a critical role for PITX2 in skeletal muscle repair and may help to develop therapeutic strategies for muscular disorders.

Keywords: PITX2; miR-31; muscle stem cells; muscular dystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Down-Regulation
  • Dystrophin / metabolism
  • Homeobox Protein PITX2
  • Homeodomain Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • MicroRNAs / metabolism
  • Models, Biological
  • Muscle Development
  • Muscular Dystrophy, Duchenne / metabolism
  • Muscular Dystrophy, Duchenne / pathology*
  • Muscular Dystrophy, Duchenne / therapy
  • Myoblasts / metabolism*
  • Myoblasts / transplantation*
  • Regeneration*
  • Satellite Cells, Skeletal Muscle / transplantation
  • Transcription Factors / metabolism*

Substances

  • Dystrophin
  • Homeodomain Proteins
  • MicroRNAs
  • Mirn31 microRNA, mouse
  • Transcription Factors