2. Academic Validation
  3. Sirt6 Mono-ADP-Ribosylates YY1 to Promote Dystrophin Expression for Neuromuscular Transmission

Sirt6 Mono-ADP-Ribosylates YY1 to Promote Dystrophin Expression for Neuromuscular Transmission

  • Adv Sci (Weinh). 2024 Nov;11(44):e2406390. doi: 10.1002/advs.202406390.
Wei Zhang 1,  Lei Bai 1,  Wentao Xu 1,  Jun Liu 2,  Yi Chen 3,  Weiqiang Lin 4,  Huasong Lu 5,  Binwei Wang 2,  Benyan Luo 3,  Guoping Peng 3,  Kejing Zhang 6,  Chengyong Shen 1 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3 Department of Neurobiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 4 Department of Nephrology, Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 5 Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 6 Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Hangzhou, 310006, China.
  • 7 MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Nanhu Brain-Computer Interface Institute, Hangzhou, China.
PMID: 39387251 DOI: 10.1002/advs.202406390
Abstract

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.

Keywords

Dystrophin; NMJ; Sirt6; YY1.

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