The Vitamin D receptor and musculoskeletal ageing: a multi-modal approach

维生素D缺乏症非常普遍，并且主要通过人口流行病学与衰老和与年龄相关的疾病中的肌肉骨骼（MSK）下降有关。尽管如此，维生素D缺乏和MSK健康之间的机械联系仍然很难定义。维生素D通过维生素D受体（VDR）发挥其许多细胞作用。我们最近发现，在大鼠电穿孔模型中，VDR的功能丧失和功能获得分别刺激骨骼肌萎缩和肥大。这些数据进一步增加了来自VDR敲除（KO）的转基因模型的证据，表明VDR调节骨骼肌质量。此外，在同一项研究中，我们发现老年人的VDR表达减少，而VDR的表达随着抗阻运动的肌肉质量增加而增加。总的来说，所有可用的数据都表明维生素D和维生素D受体依赖于肌肉质量的调节（我们的数据，自主如此）。 维生素D缺乏和VDR调节的改变与MSK衰老和许多与年龄有关的疾病有关。这可能是由于许多原因，例如不良饮食，减少阳光照射和维生素D分子到生物活性受体结合类固醇形式的混乱加工（除了年龄相关的VDR基因表达失调）。然而，需要进行后续研究来确定维生素D状态，VDR和MSK健康之间的联系。本项目将; 1）使用现有的老化/运动/固定/COPD生物库鉴定维生素D状态和MSK老化之间的新联系; 2）使用先前存在的VDR敲低细胞模型（在宿主实验室中先前产生和维持的慢病毒介导的持续VDR功能丧失）确定维生素D和维生素D非依赖性对肌肉质量的影响; 3）确定维生素D缺乏是否导致运动适应不良。

Vitamin D deficiency is highly-prevalent and has been linked - mainly through population epidemiology - to musculoskeletal (MSK) decline in both ageing, and age-related diseases. Nonetheless, mechanistic links between Vitamin D deficiency and MSK health remain poorly defined. Vitamin D exerts many of its cellular actions through the vitamin D receptor (VDR). We have recently found that loss-of-function and gain-of-function of the VDR stimulated skeletal muscle atrophy and hypertrophy, respectively, in rat electroporation models. These data add to, and further, evidence from transgenic models of VDR knockout (KO) illustrating that the VDR regulates skeletal muscle mass. Moreover, in the same study, we showed that VDR expression was reduced in older humans, while expression of the VDR increases in line with muscle mass gains in response to resistance exercise. Collectively, all available data suggest Vitamin D and Vitamin D receptor dependent regulation of muscle mass (our data, autonomously so). Vitamin D-deficiency and altered VDR regulation has been implicated in MSK ageing and many age-related diseases. This maybe for many reasons e.g. poor diet, reduced sunlight exposure and deranged processing of Vitamin D molecules to bio-active receptor binding steroid forms (in addition to age-related dysregulation of VDR gene expression). However, follow-on research is needed to define links between Vitamin D status, VDR and MSK health. The present project will; 1) identify novel links between Vitamin D status and MSK ageing, using existing ageing/exercise/immobilization/COPD bio-banks; 2) determine Vitamin D, and Vitamin D-independent effects on muscle mass using a pre-existing cell model of VDR knockdown (lentivirus-mediated sustained VDR loss-of-function previously generated and sustained, in the host-lab); 3) determine if Vitamin D deficiency leads to exercise maladaptation(s).