FOS licenses early events in stem cell activation driving skeletal muscle regeneration

Muscle satellite cells (SCs) are a quiescent (non-proliferative) stem cell population in uninjured skeletal muscle. Although SCs have been investigated for nearly 60 years, the molecular drivers that transform quiescent SCs into the rapidly dividing (activated) stem/progenitor cells that mediate muscle repair after injury remain largely unknown. Here we identify a prominent FBJ osteosarcoma oncogene (Fos) mRNA and protein signature in recently activated SCs that is rapidly, heterogeneously, and transiently induced by muscle damage. We further reveal a requirement for FOS to efficiently initiate key stem cell functions, including cell cycle entry, proliferative expansion, and muscle regeneration, via induction of pro-regenerative target genes that stimulate cell migration, division, and differentiation. Disruption of one of these Fos/AP-1 targets, NAD(+)-consuming mono-ADP-ribosyl-transferase 1 (Art1), in SCs delays cell cycle entry and impedes progenitor cell expansion and muscle regeneration. This work uncovers an early-activated FOS/ART1/mono-ADP-ribosylation (MARylation) pathway that is essential for stem cell-regenerative responses.

Automated summary

This study identified a prominent Fos mRNA and protein signature in recently activated muscle satellite cells (SCs) that is induced rapidly, heterogeneously, and transiently by muscle damage. The research further revealed the essential role of FOS in initiating key stem cell functions, including cell cycle entry, proliferative expansion, and muscle regeneration, through induction of pro-regenerative genes. Disruption of one of these Fos/AP-1 targets, Art1, delayed cell cycle entry and impeded progenitor cell expansion and muscle regeneration.