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Retinoic acid maintains human skeletal muscle progenitor cells in an immature state

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Abstract

Muscle satellite cells are resistant to cytotoxic agents, and they express several genes that confer resistance to stress, thus allowing efficient dystrophic muscle regeneration after transplantation. However, once they are activated, this capacity to resist to aggressive agents is diminished resulting in massive death of transplanted cells. Although cell immaturity represents a survival advantage, the signalling pathways involved in the control of the immature state remain to be explored. Here, we show that incubation of human myoblasts with retinoic acid impairs skeletal muscle differentiation through activation of the retinoic-acid receptor family of nuclear receptor. Conversely, pharmacologic or genetic inactivation of endogenous retinoic-acid receptors improved myoblast differentiation. Retinoic acid inhibits the expression of early and late muscle differentiation markers and enhances the expression of myogenic specification genes, such as PAX7 and PAX3. These results suggest that the retinoic-acid-signalling pathway might maintain myoblasts in an undifferentiated/immature stage. To determine the relevance of these observations, we characterised the retinoic-acid-signalling pathways in freshly isolated satellite cells in mice and in siMYOD immature human myoblasts. Our analysis reveals that the immature state of muscle progenitors is correlated with high expression of several genes of the retinoic-acid-signalling pathway both in mice and in human. Taken together, our data provide evidences for an important role of the retinoic-acid-signalling pathway in the regulation of the immature state of muscle progenitors.

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Acknowledgements

This work was supported by CNRS, INSERM, and by Montpellier University Grants. M. El Haddad was supported by a Ph.D. studentship from the Centre Hospitalier Regional Universitaire of Montpellier and the University of Montpellier. We thank Dr. Pierre Germain (Centre de Biochimie Structurale, CNRS UMR5048/INSERM U1054, Montpellier, France) for his helpful discussions.

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Authors and Affiliations

  1. Inserm U1046-UMR CNRS 9214 «Physiologie et Médecine Expérimentale du cœur et des muscles-PHYMEDEXP», CHU A. De Villeneuve, Université de Montpellier, Bâtiment Crastes de Paulet, 371 avenue du doyen Giraud, 34295, Montpellier Cedex 5, France

    Marina El Haddad, Cécile Notarnicola, Nour El Khatib, Marine Blaquière, Gérald Hugon, Jacques Mercier & Gilles Carnac

  2. Stem Cells and Development, CNRS URA 2578, Department of Developmental and Stem Cell Biology, Pasteur Institute, 25 rue du Dr Roux, 75015, Paris, France

    Brendan Evano & Shahragim Tajbakhsh

  3. INRA, UMR866, Dynamique Musculaire et Métabolisme, Université Montpellier, 34060, Montpellier, France

    Anne Bonnieu & Barbara Vernus

  4. Département de Physiologie Clinique, CHRU de Montpellier, 34295, Montpellier Cedex 5, France

    Jacques Mercier

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  1. Marina El Haddad
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Correspondence to Gilles Carnac.

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El Haddad, M., Notarnicola, C., Evano, B. et al. Retinoic acid maintains human skeletal muscle progenitor cells in an immature state. Cell. Mol. Life Sci. 74, 1923–1936 (2017). https://doi.org/10.1007/s00018-016-2445-1

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