Determinants and Outcomes of Age-related Muscle Loss

年龄相关性肌肉损失的决定因素和结果

• 批准号: 10665049
• 负责人: DOUGLAS P. KIEL
• 金额: $ 64.94万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665049
• 关键词: Acceleration; Accelerometer; Age; Amino Acids; Animals; Attenuated; Belief; Branched-Chain Amino Acids; Clinical; Cohort Studies; Communities; Creatine; Data; Diet; Dietary Proteins; Dose; Dual-Energy X-Ray Absorptiometry; Elderly; Essential Amino Acids; Excess Mortality; Fasting; Fracture; Framingham Heart Study; Genetic; Genotype; Goals; Health Care Costs; Image; Impairment; Inflammation; Ingestion; Interleukin-6; Intervention; Life Style; Measurement; Measures; Mediating; Mendelian randomization; Methods; Modeling; Morphologic artifacts; Muscular Atrophy; N-3 polyunsaturated fatty acid; Nutritional; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Physical Function; Physical activity; Plants; Polyunsaturated Fatty Acids; Process; Public Health; Publishing; Research; Rest; Risk; Risk Factors; Sample Size; Sampling; Specimen; Techniques; Technology; Testing; Thinness; Tissues; Urine; Work; age related; age-related muscle loss; cohort; disability; fall injury; falls; genetic predictors; genetic variant; genome wide association study; imaging modality; inflammatory marker; insight; instrument; men; modifiable risk; muscle form; non-genetic; novel; older men; older women; osteoporosis with pathological fracture; prevent; preventive intervention; protein intake; reduced muscle mass; skeletal muscle wasting; systemic inflammatory response; therapy development

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.

摘要 /项目摘要 对导致年龄相关肌肉质量下降及其后果下降的过程的理解一直是 从根本上限制了评估总肌肉质量的不完美方法。这减慢了发展 防止骨骼肌损失的干预措施。这项研究的长期目标是获得更好的 了解老年人总肌肉质量低的原因和后果。目标的目标 项目是通过D3-熟食稀释法来衡量总肌肉质量，并确定其与 遗传和非遗传危险因素及其与跌倒，有害跌倒和骨折的关系 基于社区的老年人。该技术提供了总肌肉的直接准确估计 单个禁食标本的质量。中心假设是总肌肉质量较低 与新型遗传变异相关，当将其用作孟德尔随机化的仪器变量时 分析将表明，较低的总肌肉质量直接增加了出现的风险下降，有害跌倒 和骨折。此外，生活方式预测因子（饮食和体育锻炼）与总肌肉质量的关联 并且随着总肌肉质量的加速损失，将部分由炎症标志物白介素-6（IL-）介导 6）。在强大的初步数据的指导下，该假设将通过追求三个特定目标进行检验 来自两个特征良好的队列的3200名参与者，弗雷明汉心脏研究（FHS）和骨质疏松 男性骨折（MROS）研究。 AIM 1将确定与总肌肉量相关的遗传变异 通过进行全基因组关联研究，通过FHS和MROS队列中的D3-酸性稀释 （GWAS）。与D3-greatine和基因分型的其他同类群体的可用性将使样本量达到8,400。 AIM 2将确定通过D3-酸稀释和入射估计的总肌肉质量之间的因果关系 通过使用在AIM 1中识别为总肌肉的仪器变量的SNP，瀑布，有害的跌倒和骨折 FHS和MROS队列中的Mendelian随机分析中的质量。 AIM 3将确定交叉 体育锻炼，饮食蛋白，必需氨基酸（EAA），分支链氨基的部分关联 FHS中的酸（BCAA）和N-3多不饱和脂肪酸（N3-PUFA），基线总肌肉质量 MROS队列以及与FHS 18个月内总肌肉质量变化的关联 队列。为了最大程度地减少混淆的机会，AIM 3还将使用先前发布的GWAS 加速度计算得出的体育活动以对得出的加速度计的孟德尔随机分析进行 体育活动和总肌肉质量。最后，AIM 3B将确定活动和 沿着IL-6描述的途径上的肌肉质量饮食。 这项研究有可能在定义减少肌肉质量的影响方面改变领域 使用有效的技术D3-熟食稀释测量，该稀释最终也可以作为药物的终点 试验。