2. Academic Validation
  3. Myomaker and ether lipids cooperate to promote fusion-competent membrane states

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

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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