Department of Neurobiology of First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, China.
Adv Sci (Weinh). 2024 Nov;11(44):e2406390. doi: 10.1002/advs.202406390. Epub 2024 Oct 10.
The degeneration of the neuromuscular junction (NMJ) and the decline in motor function are common features of aging, but the underlying mechanisms have remained largely unclear. This study reveals that Sirt6 is reduced in aged mouse muscles. Ablation of Sirt6 in skeletal muscle causes a reduction of Dystrophin levels, resulting in premature NMJ degeneration, compromised neuromuscular transmission, and a deterioration in motor performance. Mechanistic studies show that Sirt6 negatively regulates the stability of the Dystrophin repressor YY1 (Yin Yang 1). Specifically, Sirt6 mono-ADP-ribosylates YY1, causing its disassociation from the Dystrophin promoter and allowing YY1 to bind to the SMURF2 E3 ligase, leading to its degradation. Importantly, supplementation with nicotinamide mononucleotide (NMN) enhances the mono-ADP-ribosylation of YY1 and effectively delays NMJ degeneration and the decline in motor function in elderly mice. These findings provide valuable insights into the intricate mechanisms underlying NMJ degeneration during aging. Targeting Sirt6 could be a potential therapeutic approach to mitigate the detrimental effects on NMJ degeneration and improve motor function in the elderly population.
神经肌肉接头（NMJ）的退化和运动功能的下降是衰老的常见特征，但潜在的机制在很大程度上仍不清楚。本研究揭示了 Sirt6 在衰老的小鼠肌肉中减少。骨骼肌中 Sirt6 的缺失导致 Dystrophin 水平降低，导致 NMJ 过早退化、神经肌肉传递受损以及运动性能恶化。机制研究表明，Sirt6 负调控 Dystrophin 抑制剂 YY1（阴阳 1）的稳定性。具体而言，Sirt6 单 ADP-核糖基化 YY1，导致其从 Dystrophin 启动子解离，并允许 YY1 与 SMURF2 E3 连接酶结合，导致其降解。重要的是，烟酰胺单核苷酸（NMN）的补充增强了 YY1 的单 ADP-核糖基化，有效地延迟了老年小鼠 NMJ 退化和运动功能的下降。这些发现为 NMJ 退化在衰老过程中的复杂机制提供了有价值的见解。靶向 Sirt6 可能是一种潜在的治疗方法，可减轻对 NMJ 退化的不利影响并改善老年人群的运动功能。
