Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration

Viviane Tran, Sarah Nahlé, Amélie Robert, Inès Desanlis, Ryan Killoran, Sophie Ehresmann, Marie-Pier Thibault, David Barford, Kodi S. Ravichandran, Martin Sauvageau, Matthew J. Smith, Marie Kmita and Jean-François Côté ()
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Viviane Tran: Montreal Clinical Research Institute (IRCM)
Sarah Nahlé: Montreal Clinical Research Institute (IRCM)
Amélie Robert: Montreal Clinical Research Institute (IRCM)
Inès Desanlis: Montreal Clinical Research Institute (IRCM)
Ryan Killoran: Université de Montréal
Sophie Ehresmann: Montreal Clinical Research Institute (IRCM)
Marie-Pier Thibault: Montreal Clinical Research Institute (IRCM)
David Barford: MRC Laboratory of Molecular Biology
Kodi S. Ravichandran: University of Virginia
Martin Sauvageau: Montreal Clinical Research Institute (IRCM)
Matthew J. Smith: Université de Montréal
Marie Kmita: Montreal Clinical Research Institute (IRCM)
Jean-François Côté: Montreal Clinical Research Institute (IRCM)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Myoblast fusion is fundamental for the development of multinucleated myofibers. Evolutionarily conserved proteins required for myoblast fusion include RAC1 and its activator DOCK1. In the current study we analyzed the contribution of the DOCK1-interacting ELMO scaffold proteins to myoblast fusion. When Elmo1−/− mice underwent muscle-specific Elmo2 genetic ablation, they exhibited severe myoblast fusion defects. A mutation in the Elmo2 gene that reduced signaling resulted in a decrease in myoblast fusion. Conversely, a mutation in Elmo2 coding for a protein with an open conformation increased myoblast fusion during development and in muscle regeneration. Finally, we showed that the dystrophic features of the Dysferlin-null mice, a model of limb-girdle muscular dystrophy type 2B, were reversed when expressing ELMO2 in an open conformation. These data provide direct evidence that the myoblast fusion process could be exploited for regenerative purposes and improve the outcome of muscle diseases.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34806-4

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DOI: 10.1038/s41467-022-34806-4

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