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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\u2010ADP\u2010ribosylates 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\u2010ADP\u2010ribosylation 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.<\/jats:p>","DOI":"10.1002\/advs.202406390","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T10:19:22Z","timestamp":1728555562000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sirt6 Mono\u2010ADP\u2010Ribosylates YY1 to Promote Dystrophin Expression for Neuromuscular Transmission"],"prefix":"10.1002","volume":"11","author":[{"given":"Wei","family":"Zhang","sequence":"first","affiliation":[{"name":"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 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