Journal Article

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

Montagne, Benjamin, Sutcu, Haser Hasan, Ricchetti, Miria

2023

Overview

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.

• Publisher: Nature Publishing Group
• Subject: AKT protein / AKT2 protein / Caspase / DNA damage / DNA repair / DNA-dependent protein kinase / Double-strand break repair / Myogenesis / Myogenin / Protein kinase C / Satellite cells / Skeletal muscle / Transplantation