Muscle formation, growth and repair

Principal investigator: Christophe MARCELLE

Skeletal muscle | mouse and chick embryo | live-imaging | gene and cell therapy | muscle stem cell

 Our work focuses on understanding how skeletal muscles are formed and repaired in vertebrates.

We are using chick and mouse to address two main lines of investigation.
• Understanding how individual stem cells engage into differentiation or remain in a non-differentiated, quiescent and/or self-renewing state.
• To characterize the gene networks underlying the fusion of myoblasts into muscle fibers during embryonic development and muscle repair. This in turn will allow developing the tools and concepts to utilize cell fusion as a mean to repair ailing muscles in heritable muscle diseases (myopathies).

In recent years, our laboratory has focused much effort on understanding the molecular and cellular mechanisms regulating muscle cell fusion. The fusion of differentiating muscle cells to existing muscle fibers is a crucial step of muscle formation and repair that is poorly understood. We have undertaken a genome-wide functional screen on a mouse muscle cell line and identified hundreds of molecules implicated in the fusion of this cell line, with no effect on their proliferation or differentiation. Inhibitors and activators of fusion, members of various signaling pathways, genes that when mutated, lead to muscle dystrophies in human: there are many surprises within this list of putative modulators of muscle fusion. To test their function during fusion, we use the chick embryo as a model. The amenability of the chick embryo to manipulation and imaging, combined with the powerful technique of in vivo electroporation and the strong similarities of muscle formation in birds and mammals provide a unique paradigm to characterize this process in amniotes.

A second line of research is to use skeletal muscle formation in the chick embryo as a model to understand how cells within tissues display complex behaviours while being exposed to an ever-changing cellular environment. We have recently shown that in avian embryos, muscle formation is initiated by Delta1-positive neural crest cells migrating from the dorsal neural tube that, in passing, trigger NOTCH signalling and myogenesis in selected epithelial somite progenitor cells, allowing them to migrate into the nascent muscle to differentiate.

Preliminary data we have now obtained further indicate that in somite cells, the activation of the NOTCH pathway triggers a “signalling module” that couples the initiation of myogenesis with the epithelial-mesenchymal transition (EMT) that allows them to migrate into the growing muscle. This is a significant discovery: in many cellular contexts, essential cell fate decisions are associated with an EMT. This is true at many stages of embryonic development (e.g. the formation of the three germ layers during gastrulation, the formation of neural crest, etc.), but also during pathologies like the metastatic progression of carcinomas. Inhibiting EMT arrests cell fate decision in these experimental models, suggesting a mechanistic link between both processes that has never been understood. Our working hypothesis is that the signalling module we have uncovered underlies the coupling cell fate changes to EMT in a variety of developmental and pathological processes.

Chicken embryo at 5.5 days of development, clarified by the “3DISCO” technique, observed with a light sheet microscope (Z1 Zeiss, CIQLE). Green: neural crest and peripheral nervous system (anti-HNK1); Blue: dermomyotome, muscle progenitors and dorsal neural tube (anti-PAX7); Red: differentiated muscles (anti-Myosin Heavy Chain). Marie-Julie Dejardin & Christophe Marcelle.

This animation movie shows the morphogenesis and growth of the early myotome (i.e. the primitive muscle) in a chicken embryo. All muscles of the body and limbs derive from somites, which are epithelial balls of cells that form sequentially on both sides of the neural tube as the embryo develops. Shown here is the dorsal compartment of somites, named the dermomyotome, from which trunk muscles derive. In a first stage, cells from the medial, the posterior, the anterior and finally the lateral borders of the somite translocate below the dermomyotome, where they elongate parallel to the antero-posterior axis of the embryo. These elongated, mono-nucleated, post-mitotic cells are called myocytes and together they form what we have named the primary myotome. In a second stage, the central portion of the epithelial dermomyotome undergoes and epithelial-mensenchymal transition (EMT). As a result, part of the dermomyotomal cells can migrate towards the ectoderm to later form the dermis, while other cells are “parachuted” into the primary myotome. Unlike myocytes that do not divide, the parachuted cells are true muscle progenitors, and they can either differentiate or self-renew. Through this process, the muscles can grow during embryonic and fetal life. The muscle stem cells of the adult (named satellite cells) derive from the same population of progenitors identified here. It is important to realize that the same morphogenetic process takes places in mice, and therefore presumably in human. This animation movie was created in 2005 by Jérôme Gros with the free open source 3D software Blender. Publications associated with this movie: Gros, Scaal & Marcelle, Developmental Cell, 2004. Gros, Manceau, Thomé & Marcelle, Nature, 2005. Gros, Serralbo & Marcelle, Nature, 2009.

Team members

  • Christophe MARCELLEProfessor, UCBL
  • Clémence ALIBERTPhD student
  • Chloé BONNOTPhD Student
  • Emilie DELAUNE— emilie.delaune [ at ] univ-lyon1.frAssistant Professor, UCBL
  • Kathrin GIESELERProfessor, UCBL
  • Inès LATREILLEResearch Assistant, CNRS
  • Yoann LE TOQUINPhD Student
  • Valérie MORINResearch Assistant, CNRS
  • Gauthier TOULOUSEPhD Student
  • Zoé MOINIMaster 2, UCBL
  • Daria TEPORDEIMaster 2, UCBL

Selected publications

  1. Transgenic quails reveal dynamic TCF/β-catenin signaling during avian embryonic development.
    Barzilai-Tutsch H, Morin V, Toulouse G, Chernyavskiy O, Firth S, Marcelle C, Serralbo O.
    Elife (2022) — Show abstract
  2. TGFβ signalling acts as a molecular brake of myoblast fusion.
    Melendez J, Sieiro D, Salgado D, Morin V, Dejardin MJ, Zhou C, Mullen AC, Marcelle C.
    Nature Communications (2021) — Show abstract
  3. Transgenesis and web resources in quail.
    Serralbo O, Salgado D, Véron N, Cooper C, Dejardin MJ, Doran T, Gros J, Marcelle C.
    Elife (2020) — Show abstract
  4. Cytoplasmic NOTCH and membrane derived β-catenin link fate choice to epithelial-mesenchymal transition during myogenesis.
    Sieiro D, Rios AC, Hirst CE, Marcelle C.
    Elife (2016) — Show abstract
  5. A dynamic analysis of muscle fusion in the chick embryo.
    Sieiro-Mosti D, De La Celle M, Pele M, Marcelle C.
    Development (2014) — Show abstract
  6. Migrating cells mediate long-range WNT signaling.
    Serralbo O, Marcelle C.
    Development (2014) — Show abstract
  7. Neural crest regulates myogenesis through the transient activation of Notch.
    Rios AC, Serralbo O, Salgado D, Marcelle C.
    Nature (2011) — Show abstract
  8. Wnt11 acts as a directional cue to organize the elongation of early muscle fibers.
    Gros J, Serralbo O, Marcelle C.
    Nature (2009) — Show abstract
  9. Myostatin promotes the terminal differentiation of embryonic muscle progenitors.
    Manceau M, Savage K, Gros J, Thome V, McPherron A, Paterson B, Marcelle C.
    Genes Dev (2009) — Show abstract
  10. A Common Somitic Origin for Embryonic Muscle Progenitors and Satellite cells.
    Gros J, Manceau M, Thome V, Marcelle C.
    Nature (2005) — Show abstract
  11. A two step mechanism for myotome formation in chick.
    Gros J, Scaal M, Marcelle C.
    Dev Cell (2004) — Show abstract

Funding & Support

  • AFM-MyoNeurALP2 program (2022-2026) : Muscle fusion
  • Association Monégasque contre les Myopathies (2022-2025)
  • ANR (2022-2026) : Fusion of T-cells to muscle to alleviate dystrophies. ANR Partners : Frederic Relaix (Institut Mondor de recherche biomedical) , Luis Garcia (UVSQ-Université Paris-Saclay).
  • ANR/RHU (2024-2028) : AUGMENTREG project.
AFM Téléthon
Agence Nationale de la Recherche