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

Haser H Sutcu (1) , Benjamin Montagne (2) , Miria Ricchetti (2)

1 IRSN/PSE-SANTE/SERAMED/LRAcc - Laboratoire de Radiobiologie des expositions accidentelles
2 Mécanismes Moléculaires du Vieillissement Pathologique et Physiologique / Molecular Mechanisms of Pathological and Physiological Ageing

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.

Mots clés: DNA-PKcs; DNA D; MYOGENESIS; AKT; Muscle stem cells

Domaines: Biologie cellulaire

Haser H Sutcu, Benjamin Montagne, Miria Ricchetti. DNA-PKcs regulates myogenesis in an Akt-dependent manner independent of induced DNA damage. Cell Death and Differentiation, 2023, 30 (8), pp.1900-1915. ⟨10.1038/s41418-023-01177-2⟩. ⟨irsn-04288456⟩