Determinants and Outcomes of Age-related Muscle Loss

摘要/项目摘要 对导致与年龄相关的肌肉质量下降的过程及其后果的理解一直是 从根本上受限于不完善的评估总肌肉质量的方法。这减缓了发展的速度。 预防骨骼肌丧失的干预措施。这项研究的长期目标是获得更好的 了解老年人肌肉总量减少的原因和后果。这样做的目的是 项目是通过D3-肌酸稀释法测量总肌肉质量，并确定其与 遗传和非遗传危险因素及其与跌倒、损伤性跌倒和骨折的关系 以社区为基础的老年人队列。这项技术提供了对总肌肉的直接和准确的估计 来自单一空腹尿液样本的肿块。中心假设是较低的总肌肉质量是 与新的遗传变异有关，这些变异在孟德尔随机化中用作工具变量 分析将证明，较低的总肌肉质量直接增加意外跌倒、损伤性跌倒的风险 和骨折。此外，生活方式预测因素(饮食和体力活动)与总肌肉质量之间的关联 随着总肌肉质量的加速下降，炎症标志物白介素6(IL-6)将部分介导 6)。在强大的初步数据的指导下，这一假设将通过追求三个具体目标来检验，最多使用 来自弗雷明翰心脏研究(FHS)和骨质疏松症两个特征良好的队列的3200名参与者 男性骨折(MROS)研究。目标1将确定与估计的总肌肉质量相关的遗传变异 通过进行全基因组关联研究，在FHS和MROS队列中稀释D3-肌酸 提供更多的D3-肌酸队列和基因分型将使样本规模达到8,400人。 目标2将确定用D3-肌酸稀释法估计的总肌量与事件之间的因果关系 使用目标1中确定的SNPs作为总肌肉的辅助变量的跌倒、损伤性跌倒和骨折 FHS和MROS队列中孟德尔随机化分析中的质量。目标3将决定交叉点- 体力活动、膳食蛋白质、必需氨基酸、支链氨基酸的节段性关联 酸(BCAA)和n-3多不饱和脂肪酸(n-3-PUFA)与FHS和 FHS的MRO队列及其与18个月期间总肌肉质量变化的相关性 一群人。为了最大限度地减少混淆的机会，AIM 3还将使用之前发布的GWA on 加速度计派生的体力活动执行孟德尔随机化分析派生的加速度计 体力活动和总肌肉质量。最后，目标3b将确定活动的隐含间接影响和 按照IL-6描述的途径节食肌肉。 这项研究有可能在定义肌肉质量减少的影响方面改变这一领域 使用一种有效的技术D3-肌酸稀释进行测量，这最终也可以作为药物的终点 审判。

ABSTRACT / PROJECT SUMMARY The understanding of processes that lead to age-related decline in muscle mass and its consequences has been fundamentally limited by imperfect methods of assessing total muscle mass. This has slowed the development of interventions to prevent skeletal muscle loss. The long-term goal of this research is to gain a better understanding of the causes and consequences of low total muscle mass in older adults. The objectives of this project are to measure total muscle mass via the D3-creatine dilution method and determine its association with genetic and non-genetic risk factors, and their relation with falls, injurious falls and fractures in two large, community-based cohorts of older adults. This technique provides a direct and accurate estimate of total muscle mass from a single, fasting urine specimen. The central hypotheses are that lower total muscle mass is associated with novel genetic variants, which when used as instrumental variables in a Mendelian randomization analysis will demonstrate that lower total muscle mass directly increases the risk of incident falls, injurious falls and fractures. Furthermore, association of lifestyle predictors (diet and physical activity) with total muscle mass and with accelerated loss of total muscle mass will be partly mediated by inflammation marker interleukin-6 (IL- 6). Guided by strong preliminary data this hypothesis will be tested by pursuing three specific aims using up to 3,200 participants from two well-characterized cohorts, the Framingham Heart Study (FHS) and the Osteoporotic Fractures in Men (MrOS) Study. Aim 1 will identify genetic variants associated with total muscle mass estimated by D3-creatine dilution in the FHS and MrOS cohorts by performing a genome-wide association study (GWAS).The availability of additional cohorts with D3-creatine and genotyping will bring the sample size to 8,400. Aim 2 will determine the causal relation between total muscle mass estimated by D3-creatine dilution and incident falls, injurious falls and fractures by using SNPs identified in Aim 1 as instrumental variables for total muscle mass in a Mendelian Randomization analysis in the FHS and MrOS cohorts. Aim 3 will determine the cross- sectional associations of physical activity, dietary protein, essential amino acids (EAA), branched chain amino acids (BCAA) and n-3 polyunsaturated fatty acids (n3-PUFA) with baseline total muscle mass in the FHS and MrOS cohorts as well as associations with the change in total muscle mass over an 18 month period in the FHS cohort. To minimize the chance of confounding, Aim 3 will also use a previously published GWAS on accelerometry derived physical activity to perform a Mendelian Randomization analysis of accelerometry derived physical activity and total muscle mass. Lastly, Aim 3b will determine the implied indirect effect of activity and diet on muscle mass along a pathway delineated by IL-6. This study has the potential to transform the field in terms of defining the impact of reduced muscle mass measured using a valid technology, D3-creatine dilution, which could also ultimately serve as an endpoint in drug trials.