CCAAT/enhancer binding protein β is required for satellite cell self-renewal

Skelet Muscle. 2016 Dec 7;6(1):40. doi: 10.1186/s13395-016-0112-8.

Abstract

Background: Postnatal growth and repair of skeletal muscle relies upon a population of quiescent muscle precursor cells, called satellite cells that can be activated to proliferate and differentiate into new myofibers, as well as self-renew to replenish the satellite cell population. The balance between differentiation and self-renewal is critical to maintain muscle tissue homeostasis, and alterations in this equilibrium can lead to chronic muscle degeneration. The transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is expressed in Pax7+ satellite cells of healthy muscle and is downregulated during myoblast differentiation. Persistent expression of C/EBPβ upregulates Pax7, inhibits MyoD, and blocks myogenic differentiation.

Methods: Using genetic tools to conditionally abrogate C/EBPβ expression in Pax7+ cells, we examined the role of C/EBPβ in self-renewal of satellite cells during muscle regeneration.

Results: We find that loss of C/EBPβ leads to precocious differentiation at the expense of self-renewal in primary myoblast and myofiber cultures. After a single muscle injury, C/EBPβ-deficient satellite cells fail to self-renew resulting in a reduction of satellite cells available for future rounds of regeneration. After a second round of injury, muscle regeneration is impaired in C/EBPβ conditional knockout mice compared to wild-type control mice. We find that C/EBPβ can regulate Notch2 expression and that restoration of Notch activity in myoblasts lacking C/EBPβ prevents precocious differentiation.

Conclusions: These findings demonstrate that C/EBPβ is a novel regulator of satellite cell self-renewal during muscle regeneration acting at least in part through Notch2.

Keywords: C/EBPβ; MyoD; Notch; Pax7; Satellite cell; Self-renewal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Differentiation*
  • Cell Proliferation*
  • Cells, Cultured
  • Mice
  • MyoD Protein / genetics
  • MyoD Protein / metabolism
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Myoblasts / physiology
  • PAX7 Transcription Factor / genetics
  • PAX7 Transcription Factor / metabolism
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism
  • Regeneration
  • Satellite Cells, Skeletal Muscle / cytology
  • Satellite Cells, Skeletal Muscle / metabolism*
  • Satellite Cells, Skeletal Muscle / physiology

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Receptor, Notch2

Grant support