# Deciphering mechanisms of myoblast fusion

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $419,762

## Abstract

Project Summary/Abstract
Despite the importance of myoblast fusion for normal muscle development and physiology, relatively little is
known about the molecules that directly function to remodel membranes during the myoblast fusion reaction.
Elucidation of fusion mechanisms is critical to fully understand muscle development and to identify novel
therapeutic strategies to augment skeletal muscle disease. We previously discovered that myomaker (Mymk)
and myomerger (Mymx) are essential for the fusion of skeletal muscle progenitors. Moreover, ectopic
expression of these two membrane proteins induces fusion of otherwise non-fusogenic cells (fibroblasts). For
the first time, this establishes a cell-based reconstitution system with myoblast fusogens, however many
questions exist as to how these two proteins induce fusion. We have recently found that myomaker and
myomerger drive fusion through a unique cellular mechanism, by dividing their independent membrane
remodeling activities to distinctly impact the fusion process. It stands to reason that the membrane-remodeling
activities of myomaker and myomerger must be highly regulated or they could have the potential to
compromise cellular integrity. Indeed, our preliminary experiments probing the requirement of myomaker for
fusion during dystrophic disease progression unexpectedly revealed that myomaker expression in dystrophic
myofibers is deleterious. In this project we will: 1) determine the membrane-remodeling activities of myomaker
that control lipid mixing (hemifusion) 2) identify and interrogate the additional factors required for hemifusion 3)
elucidate the mechanisms by which myomerger elicits membrane stresses that drive fusion pore formation.
Additionally, we will study these fusogens in the context of chronic muscle disease (muscular dystrophy). We
will use cell biology, biochemistry, and genetic mouse models to study and define the activities of myomaker
and myomaker, thereby elucidating the mechanisms of myoblast fusion. We will also develop a reconstituted
proteoliposome system for myoblast fusion. These studies will provide unique insight into the mechanisms of
mammalian myoblast fusion. Overall, this work promises to open up a new area of investigation into the cell
biology of muscle and positively impact the possibility to harness fusion to improve regenerative medicine.

## Key facts

- **NIH application ID:** 9977331
- **Project number:** 2R01AR068286-06
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Douglas Paul Millay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,762
- **Award type:** 2
- **Project period:** 2015-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977331

## Citation

> US National Institutes of Health, RePORTER application 9977331, Deciphering mechanisms of myoblast fusion (2R01AR068286-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977331. Licensed CC0.

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