Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division

Nat Med. 2015 Dec;21(12):1455-63. doi: 10.1038/nm.3990. Epub 2015 Nov 16.

Abstract

Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asymmetric Cell Division*
  • Cell Cycle Proteins / metabolism
  • Cell Polarity*
  • Cell Proliferation
  • Cell Separation
  • Dystrophin / deficiency
  • Dystrophin / metabolism*
  • Flow Cytometry
  • Mice, Inbred mdx
  • Muscle, Skeletal / cytology*
  • Oligonucleotide Array Sequence Analysis
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Regeneration
  • Satellite Cells, Skeletal Muscle / cytology
  • Satellite Cells, Skeletal Muscle / metabolism
  • Spindle Apparatus / metabolism
  • Stem Cells / cytology*
  • Stem Cells / metabolism*

Substances

  • Cell Cycle Proteins
  • Dystrophin
  • Mark2 protein, mouse
  • Protein-Serine-Threonine Kinases