Physical performance in an animal model of vitamin D insufficiency

描述(由申请人提供)： 多达70%-80%的老年退伍军人维生素D不足(25-羟基维生素D和维生素D含量为30 ng/ml)，30%-40%的人肥胖。维生素D的状态似乎越来越多地在身体表现、身体虚弱以及最终的生活质量和死亡率方面发挥着重要作用。此外，肥胖和衰老会伴随着骨骼减少和体能下降。然而，支持这些发现的临床研究本身就含有变量，如共病、生活方式和遗传差异，这些变量使得理解特定的病理生理学非常困难。动物模型将允许阐明各种因素的贡献，因此可以更好地理解维生素D缺乏如何调节身体表现的潜在机制。据我们所知，目前还没有动物模型来探索维生素D缺乏对身体表现的影响，特别是在肥胖和高龄的背景下。我们的目标是建立一个维生素D缺乏和身体机能低下的小鼠模型。这一试点项目的结果将被用作对维生素D缺乏、肥胖、衰老和身体表现进行更广泛研究的基础，并将修改我们目前和未来的人类临床研究，以提高退伍军人的生活质量。我们假设，维生素D缺乏的小鼠的体能表现会下降，而肥胖和衰老会使其恶化。我们进一步假设这种下降的潜在机制涉及炎症和线粒体，维生素D缺乏将与炎症生物标志物增加和线粒体生物发生和功能下降相关，并且这些有害后果将在肥胖和高龄的背景下恶化。为了验证这些假说，我们将追求以下目标：1.建立健康、肥胖和老年小鼠维生素D缺乏模型。2.确定维生素D缺乏是否与体能下降、炎症增加和/或线粒体生物合成和功能下降有关。这项研究将建立一个动物模型，在该模型中，健康、肥胖和老年小鼠的血清25-OH维生素D水平将从不足到超足。这一模型将通过在4个月内补充不同的胆钙化醇(维生素D3)后的血清25-羟基D水平的测量来验证。在我们的模型建立后，我们将研究25-OH维生素D血清水平与体能(转杆表现和握力)和身体成分(DEXA扫描)结果的相关性。我们还将处死动物以恢复血清和骨骼肌，以评估炎症反应(CRP、IL-1、IL-6和TNF)、线粒体生物发生(TMRE染色和COD/SDH染色)和线粒体功能(COX活性、DFCDA染色和OXPHOS分析)。 公共卫生相关性： 这项研究的结果将对我们退伍军人和退伍军人的健康产生重大影响 医疗保健系统。我们将建立维生素D缺乏的动物模型--允许评估维生素D缺乏、肥胖和衰老对身体表现的独立和组合贡献。维生素D缺乏、肥胖和与衰老相关的残疾是越来越多的退伍军人面临的因素。我们的模型将为这些因素影响身体表现的潜在机制提供有价值的见解，并可用于优化当前和未来的人类临床研究，以产生更好的康复治疗结果。

DESCRIPTION (provided by applicant): As many as 70-80% of elderly veterans are vitamin D insufficient (25-OH vitamin D < 30 ng/ml), and 30-40 % are obese. Vitamin D status increasingly appears to play an important role in physical performance, frailty, and ultimately quality of life and mortality. In addition, obesity ad aging are accompanied by sarcopenia and decreased physical performance. However, the clinical studies that support these findings inherently contain variables, such as co-morbidities, lifestyle and genetic differences, that make it very difficult to understand the specific pathophysiology. An animal model would permit the elucidation of the contribution from various factors and therefore allow a better understanding of the underlying mechanisms of how vitamin D insufficiency modulates physical performance. To our knowledge no animal model exists to explore the impact of vitamin D insufficiency on physical performance, in particular, in the setting of obesity and advanced age. Our goal is to establish a mouse model of vitamin D insufficiency and physical performance. Results from this pilot project will be used as the basis for more extensive investigations of vitamin D insufficiency, obesity, aging and physical performance as well as to modify our current and future human clinical studies to improve the quality of life of veterans. We hypothesize that mice with vitamin D insufficiency will have decreased physical performance that is worsened by obesity and aging. We further hypothesize the underlying mechanisms for this decline involve inflammation and mitochondria and that vitamin D insufficiency will correlate with increased inflammatory biomarkers and decreases in mitochondrial biogenesis and function, and that these deleterious consequences will be worsened in the setting of obesity and advanced age. To test these hypotheses we will pursue the following aims: 1. Establish a model of vitamin D insufficiency in healthy, obese and aged mice. 2. Determine if vitamin D insufficiency is associated with reduced physical performance, increased inflammation, and/or decline in mitochondrial biogenesis and function. This study will establish an animal model where a range of serum 25-OH vitamin D levels from insufficient to hyper-sufficient will be created in healthy, obese and aged mice. This model will be verified through serum measurements of 25-OH D levels following varying supplementation of cholecalciferol (vitamin D3) over a 4 month period. Following establishment of our model we will investigate the correlation of 25-OH vitamin D serum levels with outcomes in physical performance (rotarod performance and grip strength) and body composition (DEXA scans). We will also sacrifice animals to recover serum and skeletal muscle in order to assess inflammation (CRP, IL-1, IL-6, and TNF¿), mitochondrial biogenesis (TMRE staining & COD/SDH staining), and mitochondrial function (COX activity, DFCDA staining, & OXPHOS analysis). PUBLIC HEALTH RELEVANCE: The findings of this study will have a significant impact on the health of our veterans and the VA health care system. We will establish an animal model of vitamin D insufficiency - allowing the assessment of the independent and combinatorial contributions of vitamin D insufficiency, obesity, and aging upon physical performance. Vitamin D insufficiency, obesity and the disabilities associated with aging are factors being faced by growing numbers of veterans. Our model will provide valuable insight into the underlying mechanisms by which these factors affect physical performance and can be used to optimize current and future human clinical studies to yield better therapeutic outcomes for rehabilitation.