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journal article·2024-11Open access

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

Wei Zhang, Lei Bai, Wentao Xu, Jun Liu, Yi Chen, Weiqiang Lin, Huasong Lu, Binwei Wang, Benyan Luo, Guoping Peng, Kejing Zhang, Chengyong Shen

Advanced Science· Volume 11· Issue 44
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Abstract

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.
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Research context

OpenAlex topics: Sirtuins and Resveratrol in Medicine · Adipose Tissue and Metabolism · Muscle Physiology and Disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

Department of Neurobiology First Affiliated Hospital School of Medicine Zhejiang University Hangzhou China

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

Life Sciences Institute Zhejiang University Hangzhou China

Zhejiang Provincial Key Laboratory of Pancreatic Disease MOE Joint International Research Laboratory of Pancreatic Diseases First Affiliated Hospital Hangzhou 310006 China

MOE Frontier Science Center for Brain Research and Brain‐Machine Integration Zhejiang University Nanhu Brain‐Computer Interface Institute Hangzhou China

Funding

Natural Science Foundation of Zhejiang Province · National Natural Science Foundation of China · Fundamental Research Funds for the Central Universities

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