The Sirt2-Nur77 axis regulates muscle stem cell quiescence and senescence via epigenetic-metabolic synergy.

Abstract

Nur77 expression decreases with age in multiple organs, including the liver, brain, heart, and kidney, whereas Sirt2 increases with age in the mouse cerebral cortex and hippocampus. We identified the central role of the Sirt2-P300/Nur77/K310 acetylation axis in regulating muscle homeostasis and regeneration and its age-related alterations. Consistently, we observed reduced Nur77 and elevated Sirt2 expression in aging skeletal muscle, particularly the anterior tibialis, which is enriched in type IIB and IIA fast-twitch fibers. Mechanistically, Sirt2 promoted Nur77 degradation via K310-specific deacetylation, weakening Myf5 transcriptional activity and altering satellite cell metabolic heterogeneity. Functional tests showed that Sirt2 inhibition (AGK2) or Nur77 activation (CSNB) improved muscle function in aged mice, whereas the K310R mutation led to muscle atrophy and impaired regeneration. These findings suggest the Sirt2-P300/Nur77 axis as a potential therapeutic target for skeletal muscle aging and anti-sarcopenia drug development.