Physical performance in an animal model of vitamin D insufficiency

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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.