Tamar Eigler,1 Giulia Zarfati,2 Emmanuel Amzallag,1 Sansrity Sinha,2 Nadav Segev,2 Yishaia Zabary,3 Assaf Zaritsky,3 Avraham Shakked,1 Kfir-Baruch Umansky,1 Eyal D. Schejter,4 Douglas P. Millay,5,6 Eldad Tzahor,1,7,∗ and Ori Avinoam2,∗∗


"1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
2Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
3Department of Software & Information Systems Engineering, Ben Gurion University, Be’er Sheva, Israel
4Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
5Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Eldad Tzahor: [email protected]; Ori Avinoam: [email protected]
∗Corresponding author [email protected]
∗∗Corresponding author [email protected]
7Lead contact"


Cell Biology, Molecular Biology


"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.

Keywords: myoblast fusion, myogenesis, ERK1/2, CaMKII, calcium, muscle regeneration, cultivated meat

DOI: 10.1016/j.devcel.2021.11.022


Live cell imaging (37°C, with 5% CO2) was performed using Olympus IX83 fluorescence microscope controlled via VisiView software (Visitron Systems GmbH) and equipped with CoolLED pE-4000 light source (CoolLED Ltd., UK),

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The pE-4000 Universal Illumination System offers 16 selectable wavelengths from 365 - 770 nm, making it a highly flexible illuminator covering a wide variety of fluorophores

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Dev Cell.

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