IRE1-XBP1 pathway of the unfolded protein response is required during early differentiation of C2C12 myoblasts

Yukako Tokutake, Keita Yamada, Satoko Hayashi, Wataru Arai, Takafumi Watanabe, Shinichi Yonekura

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1–XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1–XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1–XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1–XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.

Original languageEnglish
Article number182
JournalInternational journal of molecular sciences
Issue number1
Publication statusPublished - 2020 Jan 1
Externally publishedYes


  • Apoptosis
  • Autophagy
  • Skeletal muscle differentiation
  • Unfolded protein response (UPR)

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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