Fig. 6
In vivo HG intake rapidly downregulates mitochondrial activity and triggers adipogenic over osteogenic commitment in CD45− BM cells that can be rapidly and strongly reversed with oral NMN supplementation in a SIRT1-dependent fashion. A Enrichment of bone- and mitochondria-related pathways as assessed in single-cell RNA transcriptomics of uncultured BM CD45− osteolineage cells vs. MSCs harvested from young adult mice (NCBI-GEO database: GSE128423) using Metascape analysis. B Pathway analysis on the process of “function of mitochondria” involving transcription regulators with treatment of high levels of glucose as performed by MAP tool in IPA. The MAP tool showed that “function of mitochondria” is downregulated (blue) through positively regulated (orange line), negatively regulated (blue lines), and unpredicted (yellow line) downstream molecules after treatment of high levels of glucose (red). C Representative data for frequency analyses of low and intermediate mitochondrial activity as assessed in uncultured CD45− BM cells of wildtype young adult C57BL/6 mice fed normal drinking water combined with intraperitoneal (i.p.) administration of S or not, or given drinking water with additional glucose with or without NMN, or NMN combined with i.p. injection of S. D Pooled data of depolarized and polarized mitochondrial ΔΨm. as assessed in CD45− BM cells. E Pooled data for frequency analyses of low and intermediate mitochondrial activity as assessed in uncultured CD45− BM cells. F and G qPCR analyses of Cebpb and Klf5 (F) as well as Runx2 and Alpl (G) in BM cells. N = 3 for each group in all figures. Data are shown as mean ± SD. *, p < 0.05; **, p < 0.01; ***, p < 0.001. H Heatmap plots as generated comparing relative expression levels of CEBPB/Cebpb, KLF5/Klf5, OR staining, RUNX2/Runx2, ALPL/Alpl, AR staining as well as in vitro and in vivo mitochondrial activities between LG and HG groups in vitro or H2O and glucose groups in vivo. (I) Summary: HG intake for a few hours or days rapidly depresses mitochondrial activity and osteogenesis while strongly promoting adipogenesis via the NAD+/SIRT1 axis in non-senescent MSCs, with rescue of both mitochondrial activity and osteogenesis possible through NMN supplementation