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DNA-PKcs regulates myogenesis in an Akt-dependent manner independent of induced DNA damage

Cell Death & Differentiation volume 30, pages 1900–1915 (2023)Cite this article

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Abstract

Skeletal muscle regeneration relies on muscle stem (satellite) cells. We previously demonstrated that satellite cells efficiently and accurately repair radiation-induced DNA double-strand breaks (DSBs) via the DNA-dependent kinase DNA-PKcs. We show here that DNA-PKcs affects myogenesis independently of its role in DSB repair. Consequently, this process does not require the accumulation of DSBs and it is also independent of caspase-induced DNA damage. We report that in myogenic cells DNA-PKcs is essential for the expression of the differentiation factor Myogenin in an Akt2-dependent manner. DNA-PKcs interacts with the p300-containing complex that activates Myogenin transcription. We show also that SCID mice that are deficient in DNA-PKcs, and are used for transplantation and muscle regeneration studies, display altered myofiber composition and delayed myogenesis upon injury. These defects are exacerbated after repeated injury/regeneration events resulting in reduced muscle size. We thus identify a novel, caspase-independent, regulation of myogenic differentiation, and define a differentiation phase that does not involve the DNA damage/repair process.

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Fig. 1: Inhibition of DNA-PKcs blocks myogenic differentiation of satellite cells in the absence of irradiation (induced DSBs).
Fig. 2: DNA-PKcs is required for the expression of myogenin in a Akt-2 dependent manner.
Fig. 3: DNA-PKcs interacts with the complex that activates Myogenin expression, and activates Myogenin/myogenic differentiation without acting in DNA repair.
Fig. 4: Delayed SC differentiation in SCID mice results in altered muscle composition during regeneration.
Fig. 5: Marked decrease of muscle mass and increased SC population in SCID mice after multiple regeneration events.
Fig. 6: Scheme activation of Myogenin and muscle fibers before and after regeneration in WT vs SCID.

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The data analyzed during this study are included in this published article and the supplemental data files.

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Acknowledgements

We thank the lab of Shahragim Tajbakhsh for the material provided to perform in vivo muscle injuries and antibodies targeting of myogenic factors, Hiroshi Sakai for guidance to initate the in vivo injury experiments, and Shahragim Tajbakhsh for helpful discussion, Sebastien Mella for his advice on statistical analysis. We thank the Virus and Immunity Laboratory at Institut Pasteur (director Dr. Schwartz) for quantification of p24 viral particles, the components of Elisa Perdiguero-Gomez lab at Institut Pasteur, in particular Alina Sommer, for the technical help with the analysis of macrophage immunolabeling, and the center for Translational Science (CRT)- Cytometry and Biomarkers Unit and Photonic BioImaging Unit of Technology and Service (CBUTechS and PBI UTechS) at Institut Pasteur for technical support in this study.

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This work was supported by AFM (research grant (16580), and thesis grant (18425)).

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  1. Haser Hasan Sutcu

    Present address: Institut de Radioprotection et de Sûrété Nucléaire (IRSN), Radiobiology of Accidental Exposure Laboratory (PSE-SANTE/SERAMED/LRAcc), B.P. 17, 92262 Fontenay-aux-Roses, Cedex, France

Authors and Affiliations

  1. Institut Pasteur, Team Stability of Nuclear & Mitochondrial DNA, Department of Developmental and Stem Cell Biology, CNRS UMR3738, 75015, Paris, France

    Haser Hasan Sutcu, Benjamin Montagne & Miria Ricchetti

  2. Université Pierre et Marie Curie (Sorbonne Universities, ED515), Paris, France

    Haser Hasan Sutcu

  3. Institut Pasteur, Molecular Mechanisms of Pathological and Physiological Ageing, Department of Developmental and Stem Cell Biology, Paris, France

    Benjamin Montagne & Miria Ricchetti

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HHS planned, analyzed, and performed all experiments, except the immunostaining of macrophages, fiber composition (slow and fast fibers), and some experiments with the caspase inhibitor, which have been performed by BM. HHS also contributed to writing the manuscript. MR supervised the study, analyzed the data, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Miria Ricchetti.

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Sutcu, H.H., Montagne, B. & Ricchetti, M. DNA-PKcs regulates myogenesis in an Akt-dependent manner independent of induced DNA damage. Cell Death Differ 30, 1900–1915 (2023). https://doi.org/10.1038/s41418-023-01177-2

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