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.
方法:使用人细胞信息对MSC分化过程中涉及的能量通路进行生物信息学分析。使用多源非衰老的人和鼠MSCs评估了正常与高葡萄糖(HG)条件对骨/脂肪谱系定型和线粒体功能的体外解剖;用于体内验证,用正常或添加HG的水喂养幼鼠,随后分析骨髓CD45-MSC。
结果:生物信息学分析显示,线粒体和葡萄糖相关的代谢途径是MSC骨/脂肪谱系确定的组成部分。功能上,由于烟酰胺腺嘌呤二核苷酸(NAD+)的消耗,单独的体外HG降低了MSC线粒体活性和骨生成,同时增强了8小时的脂肪形成,Sirtuin(SIRT)1的重要线粒体辅酶和辅因子,Sirtuin是一种也参与成骨的长寿基因。在体内,年轻小鼠中HG的摄入量耗尽MSCNAD+,口服NAD前体补充剂在1〜5天内以SIRT1依赖性方式迅速逆转线粒体下降和骨/脂肪承诺。
结论:我们发现了过量葡萄糖的惊人快速影响,单一的饮食因素,在年轻环境中MSCSIRT1功能和成骨,以及NAD+-单分子对MSC线粒体功能和谱系承诺的关键作用。鉴于当前全球单糖的过度消费,这些发现对未来的全球OP和残疾风险具有重要意义。