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.

Public Health Relevance

Fusion of myoblasts is an essential process for muscle development and regeneration. The goal of this project is to explore the mechanisms of myomaker and myomerger action during myoblast fusion and to understand their role during chronic disease. !

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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Cincinnati Children's Hospital Medical Center
United States
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Leikina, Evgenia; Gamage, Dilani G; Prasad, Vikram et al. (2018) Myomaker and Myomerger Work Independently to Control Distinct Steps of Membrane Remodeling during Myoblast Fusion. Dev Cell 46:767-780.e7
Sampath, Srihari C; Sampath, Srinath C; Millay, Douglas P (2018) Myoblast fusion confusion: the resolution begins. Skelet Muscle 8:3
Goh, Qingnian; Millay, Douglas P (2017) Requirement of myomaker-mediated stem cell fusion for skeletal muscle hypertrophy. Elife 6:
Gamage, Dilani G; Leikina, Eugenia; Quinn, Malgorzata E et al. (2017) Insights into the localization and function of myomaker during myoblast fusion. J Biol Chem 292:17272-17289
Quinn, Malgorzata E; Goh, Qingnian; Kurosaka, Mitsutoshi et al. (2017) Myomerger induces fusion of non-fusogenic cells and is required for skeletal muscle development. Nat Commun 8:15665
Mitani, Yasuyuki; Vagnozzi, Ronald J; Millay, Douglas P (2017) In vivo myomaker-mediated heterologous fusion and nuclear reprogramming. FASEB J 31:400-411
Millay, Douglas P; Gamage, Dilani G; Quinn, Malgorzata E et al. (2016) Structure-function analysis of myomaker domains required for myoblast fusion. Proc Natl Acad Sci U S A 113:2116-21