Myomaker and ether lipids cooperate to promote fusion-competent membrane states

  • Cell Rep. 2026 Feb 24;45(2):116900. doi: 10.1016/j.celrep.2025.116900.
Tanner J Wherley  1 ,  Xueheng Zhao  2 ,  Sajedah M Hindi  1 ,  Laura J S Lopes  3 ,  Evgenia Leikina  4 ,  Fiona C Rowan  1 ,  Kenneth D R Setchell  2 ,  Alexander J Sodt  3 ,  Leonid V Chernomordik  4 ,  Douglas P Millay  5
Affiliations
  • 1. Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 2. Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 3. Unit on Membrane Chemical Physics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
  • 4. Section on Membrane Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
  • 5. Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Electronic address: [email protected].
PMID: 41575859 DOI: 10.1016/j.celrep.2025.116900
Abstract

Cell fusion is a fundamental process for skeletal muscle development and regeneration. The muscle-specific fusogens Myomaker and Myomerger are necessary for fusion of muscle cells and together are sufficient for fusion. A mechanistic understanding of Myomaker activity is lacking. Here, we identify ether-linked Phospholipids as modulators of Myomaker activity. Although Myomaker shows homology to ceramidases, we observe no ability for the protein to regulate ceramides. Treatment of myocytes with a ceramide synthase inhibitor increases fusion, and lipidomic analysis reveals an increase in cellular ether lipids. Using a lentiviral pseudotyping system to isolate Myomaker-containing membranes, we find an enrichment of ether lipids. Elevating ether lipids in Myomaker-expressing cells induces fusion, even without Myomerger, and correlates with cell surface exposure of phosphatidylethanolamine and phosphatidylserine, indicating a role for Myomaker in remodeling plasma membrane lipid distribution. These findings reveal a link between lipid asymmetry and the molecular machinery responsible for muscle cell fusion.

Keywords
CP: Cell biology; Myomaker; cell fusion; ceramides; ether lipids; myoblast fusion.
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