ERK1/2 inhibition promotes robust myotube growth via CaMKII activation resulting in myoblast-to-myotube fusion

Tamar Eigler, Giulia Zarfati, Emmanuel Amzallag, Sansrity Sinha, Nadav Segev, Yishaia Zabary, Assaf Zaritsky, Avraham Shakked, Kfir Baruch Umansky, Eyal D. Schejter, Douglas P. Millay, Eldad Tzahor, Ori Avinoam

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Myoblast fusion is essential for muscle development and regeneration. Yet, it remains poorly understood how mononucleated myoblasts fuse with preexisting fibers. We demonstrate that ERK1/2 inhibition (ERKi) induces robust differentiation and fusion of primary mouse myoblasts through a linear pathway involving RXR, ryanodine receptors, and calcium-dependent activation of CaMKII in nascent myotubes. CaMKII activation results in myotube growth via fusion with mononucleated myoblasts at a fusogenic synapse. Mechanistically, CaMKII interacts with and regulates MYMK and Rac1, and CaMKIIδ/γ knockout mice exhibit smaller regenerated myofibers following injury. In addition, the expression of a dominant negative CaMKII inhibits the formation of large multinucleated myotubes. Finally, we demonstrate the evolutionary conservation of the pathway in chicken myoblasts. We conclude that ERK1/2 represses a signaling cascade leading to CaMKII-mediated fusion of myoblasts to myotubes, providing an attractive target for the cultivated meat industry and regenerative medicine.

Original languageEnglish
Pages (from-to)3349-3363.e6
JournalDevelopmental Cell
Volume56
Issue number24
DOIs
StatePublished - 20 Dec 2021

Keywords

  • CaMKII
  • ERK1/2
  • calcium
  • cultivated meat
  • muscle regeneration
  • myoblast fusion
  • myogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (all)
  • Developmental Biology
  • Cell Biology

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