Chlebek Carolyn, McNeill Tyler J, Huang Muyin, Raynor Maia S, van der Meulen Marjolein C H
Meinig School of Biomedical Engineering, Cornell University, 121 Weill Hall, Ithaca, NY, 14853, USA.
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA.
Sci Rep. 2025 May 31;15(1):19134. doi: 10.1038/s41598-025-02141-5.
Mechanical loading induces bone formation in young rodents, but mechanoresponsiveness is reduced with age. Glycolytic activity and mitochondrial dysfunction increase with age and may change bone mechanotransduction. To evaluate load-induced changes to bioenergetic activity in young and adult animals, we loaded the tibia of 10-wk and 26-wk female C57BL/6J mice and examined transcriptomic responses at the mid-diaphysis, and metaphyseal cortical shell and cancellous core. Across all biological processes, oxidative phosphorylation and mitochondrial pathways were most often enriched with loading and had contrasting enrichment in young and adult animals. Following loading, young animals had temporally-coordinated differential expression of mitochondrial-associated genes, with greatest expression at the mid-diaphysis. In adults, bioenergetic gene expression was lower compared to young animals. To assess individual contributions of glycolysis and pyruvate-mediated oxidative phosphorylation to load-induced bone formation in vivo, we inhibited each pathway therapeutically and loaded the tibia of young and adult female mice for 2 weeks. In both young and adult mice, loading increased cortical bone mass, but inhibition of oxidative phosphorylation reduced cortical area and moment of inertia in both loaded and control limbs. Conversely, load-induced improvements of adult cancellous bone depended on glycolysis. In summary, mechanical loading transcriptionally activated mitochondrial pathways in an age-specific manner and bioenergetic inhibition revealed unique metabolic programs for cortical and cancellous bone.
机械负荷可诱导幼年啮齿动物的骨形成，但机械反应性会随着年龄增长而降低。糖酵解活性和线粒体功能障碍会随着年龄增长而增加，可能会改变骨的机械转导。为了评估负荷对幼年和成年动物生物能量活性的影响，我们对10周龄和26周龄雌性C57BL/6J小鼠的胫骨施加负荷，并检查骨干中部、干骺端皮质壳和松质骨核心处的转录组反应。在所有生物过程中，氧化磷酸化和线粒体途径在负荷后最常富集，且在幼年和成年动物中有相反的富集情况。负荷后，幼年动物线粒体相关基因有时间上协调的差异表达，在骨干中部表达最高。在成年动物中，生物能量基因表达低于幼年动物。为了评估糖酵解和丙酮酸介导的氧化磷酸化对体内负荷诱导的骨形成的个体贡献，我们通过治疗性抑制每条途径，并对幼年和成年雌性小鼠的胫骨施加负荷2周。在幼年和成年小鼠中，负荷均增加了皮质骨质量，但抑制氧化磷酸化会降低负荷和对照肢体的皮质面积和惯性矩。相反，负荷诱导的成年松质骨改善依赖于糖酵解。总之，机械负荷以年龄特异性方式转录激活线粒体途径，生物能量抑制揭示了皮质骨和松质骨独特的代谢程序。
