Determinants and Outcomes of Age-related Muscle Loss

摘要/项目总结 对导致与年龄相关的肌肉质量下降及其后果的过程的理解一直是 从根本上受到评估总肌肉质量的不完善方法的限制。这减缓了发展速度 干预措施来防止骨骼肌损失。本研究的长期目标是获得更好的 了解老年人总肌肉质量低的原因和后果。这一目标 项目是通过D3-肌酸稀释法测量总肌肉质量，并确定其与 遗传和非遗传风险因素，以及它们与福尔斯、损伤性福尔斯和骨折的关系， 以社区为基础的老年人群体。这项技术提供了一个直接和准确的估计总肌肉 一个空腹尿样的肿块中心假设是，较低的总肌肉质量是 与新的遗传变异相关，当用作孟德尔随机化中的工具变量时， 分析将证明，较低的总肌肉质量直接增加了意外福尔斯、伤害性福尔斯 和骨折此外，生活方式预测因素（饮食和体育活动）与总肌肉质量的关联 并且总肌肉质量的加速损失将部分由炎症标志物白细胞介素-6（IL-6）介导。 6）。在强有力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， 来自两个特征良好的队列的3，200名参与者，Frachial Heart研究（FHS）和骨质疏松研究（Osteoporotic Study）。 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队列中通过D3-肌酸稀释 具有D3-肌酸和基因分型的额外群组的可用性将使样本量达到8，400。 目标2将确定通过D3-肌酸稀释估计的总肌肉质量与事件之间的因果关系 福尔斯、损伤性福尔斯和骨折，使用目标1中确定的SNP作为总肌肉的工具变量 在FHS和MrOS队列中进行孟德尔随机化分析。目标3将决定十字架- 体力活动、膳食蛋白质、必需氨基酸、支链氨基酸 FHS中的支链氨基酸（BCAA）和n-3多不饱和脂肪酸（n3-PUFA）与基线总肌肉质量， MrOS队列以及与FHS中18个月期间总肌肉质量变化的相关性 队列。为了最大限度地减少混淆的机会，Aim 3还将使用先前发表的GWAS， 加速度计衍生的身体活动，以执行加速度计衍生的孟德尔随机化分析。 体力活动和总肌肉量。最后，目标3b将确定活动的间接影响， 饮食对肌肉质量沿着由IL-6描绘的途径。 这项研究有可能在定义肌肉质量减少的影响方面改变该领域 使用有效的技术，D3-肌酸稀释，这也可以最终作为药物治疗的终点， 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.