仅过量葡萄糖就会在数小时/数天内通过 NAD+/SIRT1 轴抑制年轻间充质基质/干细胞的成骨和线粒体活性。

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-05-13 DOI:10.1186/s12929-024-01039-0
B Linju Yen, Li-Tzu Wang, Hsiu-Huang Wang, Chin-Pao Hung, Pei-Ju Hsu, Chia-Chi Chang, Chien-Yu Liao, Huey-Kang Sytwu, Men-Luh Yen
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引用次数: 0

摘要

背景:全球过量摄入单糖对骨骼健康的影响尚不清楚,这种影响在青春期/成年早期达到高峰,并与骨质疏松症(OP)和骨折风险数十年相关。间充质基质/干细胞(MSCs)是成骨细胞/成骨细胞的祖细胞,已知其成骨分化能力会随着年龄的增长而降低。令人担忧的是,虽然有相关证据表明,摄入单糖最多的青少年骨量最低,但对这种相关性的因果关系还没有机制性的认识:方法:利用人体细胞信息对间叶干细胞分化过程中涉及的能量途径进行生物信息学分析。方法:利用人体细胞信息对间叶干细胞分化过程中涉及的能量通路进行生物信息学分析;利用多种来源的非衰老人和小鼠间叶干细胞,评估正常与高糖(HG)条件对骨/髓系形成和线粒体功能的影响;为了进行体内验证,给幼鼠喂食正常或添加 HG 的水,随后对骨髓 CD45- 间叶干细胞进行分析:结果:生物信息学分析表明,线粒体和葡萄糖相关代谢途径是间充质干细胞骨/髓系定向不可或缺的组成部分。在功能上,体外单用 HG 而不诱导分化会降低间充质干细胞线粒体活性和骨生成,同时在 8 小时后会增强脂肪生成,这是由于烟酰胺腺嘌呤二核苷酸(NAD+)耗竭所致,NAD+ 是一种重要的线粒体辅酶,也是 Sirtuin(SIRT)1 的辅助因子,SIRT 是一种长寿基因,也参与骨生成。在体内,年轻小鼠摄入的 HG 会耗尽间充质干细胞 NAD+,而口服 NAD+前体补充剂可在 1 ~ 5 天内以 SIRT1 依赖性方式迅速逆转线粒体衰退和骨/脂肪承诺:我们发现过量的葡萄糖(一种单一的膳食因素)对间充质干细胞 SIRT1 功能和年轻时的成骨过程有惊人的快速影响,而且 NAD+(一种单一的分子)对间充质干细胞线粒体功能和血统承诺都起着至关重要的作用。鉴于目前全球范围内对单糖的过度摄入,这些发现对未来全球OP和残疾风险具有重要意义。
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Excess glucose alone depress young mesenchymal stromal/stem cell osteogenesis and mitochondria activity within hours/days via NAD+/SIRT1 axis.

Background: The impact of global overconsumption of simple sugars on bone health, which peaks in adolescence/early adulthood and correlates with osteoporosis (OP) and fracture risk decades, is unclear. Mesenchymal stromal/stem cells (MSCs) are the progenitors of osteoblasts/bone-forming cells, and known to decrease their osteogenic differentiation capacity with age. Alarmingly, while there is correlative evidence that adolescents consuming greatest amounts of simple sugars have the lowest bone mass, there is no mechanistic understanding on the causality of this correlation.

Methods: Bioinformatics analyses for energetics pathways involved during MSC differentiation using human cell information was performed. In vitro dissection of normal versus high glucose (HG) conditions on osteo-/adipo-lineage commitment and mitochondrial function was assessed using multi-sources of non-senescent human and murine MSCs; for in vivo validation, young mice was fed normal or HG-added water with subsequent analyses of bone marrow CD45- MSCs.

Results: Bioinformatics analyses revealed mitochondrial and glucose-related metabolic pathways as integral to MSC osteo-/adipo-lineage commitment. Functionally, in vitro HG alone without differentiation induction decreased both MSC mitochondrial activity and osteogenesis while enhancing adipogenesis by 8 h' time due to depletion of nicotinamide adenine dinucleotide (NAD+), a vital mitochondrial co-enzyme and co-factor to Sirtuin (SIRT) 1, a longevity gene also involved in osteogenesis. In vivo, HG intake in young mice depleted MSC NAD+, with oral NAD+ precursor supplementation rapidly reversing both mitochondrial decline and osteo-/adipo-commitment in a SIRT1-dependent fashion within 1 ~ 5 days.

Conclusions: We found a surprisingly rapid impact of excessive glucose, a single dietary factor, on MSC SIRT1 function and osteogenesis in youthful settings, and the crucial role of NAD+-a single molecule-on both MSC mitochondrial function and lineage commitment. These findings have strong implications on future global OP and disability risks in light of current worldwide overconsumption of simple sugars.

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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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