中国科学院上海营养与健康研究所应浩课题组的一项最新研究发现miR-183和miR-96介导的NAD⁺亚细胞分配调节肌肉干细胞分化。该项研究成果发表在2026年3月31日出版的《分子细胞生物学》上。

在这项研究中，该课题组证明miR-183和miR-96的缺失导致损伤后骨骼肌再生效率低下，并引发MuSC来源的原代成肌细胞过早分化。潜在的机制涉及通过靶向SLC25A51介导的miRNA调节，SLC25A51是一种线粒体NAD⁺转运体，可提高线粒体NAD⁺水平，同时降低细胞质NAD⁺水平。他们的研究结果表明，胞质NAD⁺的减少减少了sirt1介导的去乙酰化，增加了肌生成基因启动子上的H4K16ac，从而促进分化。同时，线粒体NAD⁺的积累刺激三羧酸循环，导致ATP和柠檬酸水平升高。这些代谢物变构激活ACLY途径，进而增加乙酰辅酶A的产生，从而为H4K16ac提供乙酰基。

此外，SIRT3敲低会损害miR-183/96缺陷细胞的肌源性分化，并减弱ATP和乙酰辅酶A水平的升高，这表明线粒体NAD⁺的升高也通过SIRT3介导的线粒体代谢和乙酰辅酶A产生的调节来增强分化。他们的研究表明，miR-183和miR-96是表观遗传代谢网络的关键调节因子，通过NAD⁺的亚细胞分配影响MuSC分化，确保适当的再生时机。

据了解，作为一种重要的代谢辅助因子，细胞内NAD⁺的丰度对细胞干细胞（MuSC）的功能有重要影响。然而，NAD⁺的空间调控及其对MuSC功能的影响尚不清楚。

附：英文原文

Title: NAD+ subcellular partitioning mediated by miR-183 and miR-96 regulates muscle stem cell differentiation

Author: Ma, Mei, Ma, Ruisen, Li, Zhuoyang, Shen, Siyi, Kong, Wenqing, Qiu, Tianyuan, Niu, Zhoumin, Chen, Jingjing, Wu, Yuting, Li, Yan, Jin, Zi-Bing, Li, Yuying, Ying, Hao

Issue&Volume: 2026-03-31

Abstract: The intracellular abundance of NAD+, a vital metabolic cofactor, critically influences muscle stem cell (MuSC) function. However, the spatial regulation of NAD+ and its impact on MuSC function remain unclear. In this study, we demonstrated that the loss of miR-183 and miR-96 leads to inefficient skeletal muscle regeneration upon injury and triggers premature differentiation of MuSC-derived primary myoblasts. The underlying mechanism involves miRNA-mediated regulation through targeting SLC25A51, a mitochondrial transporter for NAD+ that elevates mitochondrial NAD+ while reducing cytoplasmic NAD+ levels. Our results suggest that the reduction in cytoplasmic NAD+ diminishes SIRT1-mediated deacetylation, increasing H4K16ac at the promoters of myogenic genes to promote differentiation. Concurrently, the mitochondrial NAD+ accumulation stimulates the tricarboxylic acid cycle, leading to elevated levels of ATP and citrate. These metabolites allosterically activate the ACLY pathway, which in turn increases acetyl-CoA production, thereby supplying acetyl groups for H4K16ac. Furthermore, SIRT3 knockdown impaired myogenic differentiation and attenuated the increased levels of both ATP and acetyl-CoA in miR-183/96-deficient cells, suggesting that the elevated mitochondrial NAD+ also enhances differentiation via SIRT3-mediated regulation of mitochondrial metabolism and acetyl-CoA production. Our work establishes miR-183 and miR-96 as critical regulators of epigenetic–metabolic networks that influence MuSC differentiation through subcellular partitioning of NAD+, ensuring proper regeneration timing.

DOI: 10.1093/jmcb/mjag015

Source: https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjag015/8566319searchresult=1