Histone lactylation antagonizes senescence and skeletal muscle aging via facilitating gene expression reprogramming [snRNA-seq]

ABSTRACT: Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. Many studies have investigated the histone modification mechanisms that regulate cellular senescence and aging. In this study, we show that histone lactylation, an identified histone modification that integrates metabolic processes, epigenetic regulation of gene expression and cellular activities in response to internal and external cues, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways, thereby inhibiting cellular senescence. Furthermore, the modulation of enzymes crucial for histone lactylation, including p300 and HDAC1, leads to reduced histone lactylation and accelerated cellular senescence. Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Running exercise increases the levels of glycolysis and histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways, thereby helping to preserve the proper function of skeletal muscle. Our study highlights the significant roles of histone lactylation in modulating cellular senescence as well as aging-related tissue function, suggesting that this modification may serve as an innovative biomarker for senescence and provides a promising avenue for antiaging intervention via metabolic manipulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE226007 | GEO | 2024/05/01

REPOSITORIES: GEO