Dual function of VGLL4 in muscle regeneration

EMBO J. 2019 Sep 2;38(17):e101051. doi: 10.15252/embj.2018101051. Epub 2019 Jul 22.

Abstract

VGLL4 has previously been identified as a negative regulator of YAP. Here we show that VGLL4 regulates muscle regeneration in both YAP-dependent and YAP-independent manners at different stages. Knockout of VGLL4 in mice leads to smaller myofiber size and defective muscle contraction force. Furthermore, our studies reveal that knockout of VGLL4 results in increased muscle satellite cells proliferation and impaired myoblast differentiation, which ultimately leads to delayed muscle regeneration. Mechanistically, the results show that VGLL4 works as a conventional repressor of YAP at the proliferation stage of muscle regeneration. At the differentiation stage, VGLL4 acts as a co-activator of TEAD4 to promote MyoG transactivation and facilitate the initiation of differentiation in a YAP-independent manner. Moreover, VGLL4 stabilizes the protein-protein interactions between MyoD and TEAD4 to achieve efficient MyoG transactivation. Our findings define the dual roles of VGLL4 in regulating muscle regeneration at different stages and may open novel therapeutic perspectives for muscle regeneration.

Keywords: MyoD; MyoG; TEAD4; VGLL4; muscle regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • DNA-Binding Proteins / metabolism
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / physiology*
  • MyoD Protein / metabolism
  • Myogenin / metabolism
  • Regeneration*
  • Satellite Cells, Skeletal Muscle / cytology
  • Satellite Cells, Skeletal Muscle / metabolism
  • TEA Domain Transcription Factors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Muscle Proteins
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Myog protein, mouse
  • Myogenin
  • TEA Domain Transcription Factors
  • Tead4 protein, mouse
  • Transcription Factors
  • VGLL4 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse