Early-life NAD? deficiency programs skeletal muscle aging via epigenetic downregulation of hyaluronic acid synthesis
Nicotinamide adenine dinucleotide (NAD+) levels decline with age, which has been associated with the development of aging-associated diseases. However, it remains unknown whether low NAD+ levels in early life affect aging. This study demonstrates that deficiency of NAD synthetase (NADS), a critical enzyme of the deamidated NAD+ biosynthesis pathway, drastically reduced NAD+ levels in skeletal muscle and impaired muscle function at a young age. Intriguingly, NAD+ levels were restored to normal in middle-aged NADS knockout mice, whereas muscle function remained compromised. Gene expression analysis identified that hyaluronic acid synthase 2 (Has2) was downregulated in both young NADS knockout mice and aged wild-type mice. We also revealed that Has2 was epigenetically downregulated via the a-ketoglutarate-JMJD3 axis. Then, impaired hyaluronic acid signaling dampened muscle stem cell, leading to decreased locomotor activity. These results suggest that maintaining NAD+ levels during early life is important for promoting healthy aging in skeletal muscle. Overall design: ChIP sequencing with anti-H3K27me3 antibody using the skeletal muscle samples from young WT and NADS KO mice.