PAX3 Confers Functional Heterogeneity in Skeletal Muscle Stem Cell Responses to Environmental Stress

Cell Stem Cell. 2019 Jun 6;24(6):958-973.e9. doi: 10.1016/j.stem.2019.03.019. Epub 2019 Apr 18.


Muscle satellite cells (MuSCs) are the quiescent muscle stem cells required for adult skeletal muscle repair. The impact of environmental stress such as pollution on MuSC behavior remains unexplored. We evaluated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, a ubiquitous and highly toxic pollutant, on MuSCs by combining in vivo mouse molecular genetic models with ex vivo studies. While all MuSCs express the transcription factor PAX7, we show that a subset also express PAX3 and exhibit resistance to environmental stress. Upon systemic TCDD treatment, PAX3-negative MuSCs display impaired survival, atypical activation, and sporadic differentiation through xenobiotic aryl hydrocarbon receptor signaling. We further show that PAX3-positive MuSCs become sensitized to environmental stress when PAX3 function is impaired and that PAX3-mediated induction of mTORC1 is required for protection. Our study, therefore, identifies a functional heterogeneity of MuSCs in response to environmental stress controlled by PAX3.

Keywords: AHR; G(alert); PAX3; TCDD; environmental stress; muscle stem cells; satellite cells; skeletal muscle.

Publication types

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

MeSH terms

  • Adult Stem Cells / physiology*
  • Animals
  • Cell Differentiation
  • Cell Survival
  • Cells, Cultured
  • Environmental Pollution / adverse effects*
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PAX3 Transcription Factor / genetics
  • PAX3 Transcription Factor / metabolism*
  • PAX7 Transcription Factor / genetics
  • PAX7 Transcription Factor / metabolism*
  • Polychlorinated Dibenzodioxins / adverse effects*
  • Receptors, Aryl Hydrocarbon / metabolism
  • Satellite Cells, Skeletal Muscle / physiology*
  • Signal Transduction


  • PAX3 Transcription Factor
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Pax3 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1