Study of Muscle, Mobility and Aging (SOMMA)

肌肉、活动能力和衰老研究 (SOMMA)

基本信息

批准号：
10441623
负责人：
STEVEN RON CUMMINGS
金额：
$ 513.29万
依托单位：
CALIFORNIA PACIFIC MED CTR RES INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441623
关键词：
Address Affect Age Aging Animal Model Autophagocytosis Biological Biopsy Blood Clinical Communities Complex Contractile Proteins Contracts Creatine Data Denervation Dependence Dual-Energy X-Ray Absorptiometry Elderly Enrollment Fresh Tissue Gait speed Gene Cluster Gene Expression Gene Expression Profile Generations Genetic Transcription Glycolysis Gold Health Care Costs Human Image Impairment Individual Intervention Knowledge Laboratories Laboratory Study Locomotion Longitudinal Studies Magnetic Resonance Imaging Measurement Measures Methods Mitochondria Muscle Muscle Contraction Muscle Fibers Muscular Atrophy Organelles Outcome Oxidative Phosphorylation Pathway interactions Pattern Persons Physical activity Play Property Prospective Studies Quality Control Quality of life Records Research Research Design Risk Role Science Skeletal Muscle Societies Speed Stimulus Technology Testing Thinness Tissues Walking Woman age related base clinical phenotype disability disability risk exercise regimen fitness forest individual variation innovation macromolecule member men meter muscle aging muscle form new therapeutic target novel oxidative damage prevent prospective quadriceps muscle recruit reduced muscle mass sarcopenia tissue archive transcriptome transcriptome sequencing transcriptomics walking speed

项目摘要

Mobility inevitably declines with age, more in some than other people, often leading to mobility disability with dependency, decreased quality of life, and enormous health care costs. The role of age-related biological changes in skeletal muscle on the decline in mobility is poorly understood. We hypothesize that muscle mass and the capacity to produce ATP are strong determinants of the mobility disability in older adults. Based on advances from laboratory studies of muscle aging, we also hypothesize that denervation, oxidative damage, and decreased autophagic flux interact and contribute to declines in fitness, endurance and an increased risk of mobility disability. We will also use transcriptomic profiling by RNAseq to discover patterns of gene expression that play important roles in the loss of mobility with aging. In the Study of Muscle Mobility and Aging (SOMMA), a prospective, longitudinal study of men and women age 70 to 90, our team of experts in clinical and laboratory sciences will use innovative and state-of- the-art technologies with rigorous quality control to test these hypotheses and discover new pathways for the loss of mobility with aging. We will measure quadriceps contractile volume by MRI and total muscle mass by d3 creatine dilution. We will use 31PMRS to assess the capacity of the quadriceps to generate ATP (ATPmax). In tissue form, muscle biopsies quantify denervation and oxidative damage to contractile proteins. SOMMA will be the first to quantify autophagic flux to assess the role of autophagy in the loss of mobility with aging. We use respirometry on fresh tissue to quantify the contribution of mitochondria to ATPmax and mobility disability. These properties interact: for example, decreased autophagic flux promotes the accumulation of oxidative damage and denervation, and understanding these relationships will guide the analysis and interpretation of our results. Furthermore, we will use unbiased RNA-sequencing (RNA-seq) to profile the entire transcriptome to discover new associations between clusters of genes and individual variation in rates of loss of fitness (peak VO2), muscle mass, and risk of mobility disability. Field centers at Wake Forest and Pittsburgh, with exceptional track records for recruiting and retaining older adults in complex studies, will enroll 875 women and men age 70–89 with a gait speed ≤ 1.0 m/s, providing sufficient power to identify important relationships between individual and combinations of properties and the risk of mobility disability. SOMMA may identify and prioritize targets for new therapeutics and tailored exercise regimens. We also will create a unique archive of tissue, blood, with longitudinal data about important clinical outcomes that the scientific community can use to efficiently test new hypotheses about muscle and loss of mobility with aging.

随着年龄的增长，行动能力不可避免地下降，某些人比其他人更严重，常常导致行动障碍依赖、生活质量下降以及与年龄相关的生物学的巨大医疗费用。我们对骨骼肌变化对活动能力下降的影响知之甚少。和产生 ATP 的能力是老年人行动障碍的重要决定因素。随着肌肉老化实验室研究的进展，我们还研究了去神经作用、氧化损伤、和自噬流减少相互作用，导致健康、耐力下降和风险增加我们还将使用 RNAseq 进行转录组分析来发现基因模式。表达在随着衰老而丧失活动能力方面发挥重要作用。在肌肉活动性和衰老研究 (SOMMA) 中，一项针对男性和女性的前瞻性纵向研究针对 70 至 90 岁的女性，我们的临床和实验室科学专家团队将使用创新和最先进的技术最先进的技术和严格的质量控制来测试这些假设并发现新的途径我们将通过 MRI 测量股四头肌收缩量，并通过以下方法测量总肌肉质量。 d3 肌酸稀释液我们将使用 31PMRS 来评估股四头肌产生 ATP (ATPmax) 的能力。在组织形式中，肌肉活检可量化 SOMMA 的去神经支配和氧化损伤。成为第一个量化自噬通量以评估自噬在衰老过程中活动能力丧失中的作用的人。对新鲜组织进行呼吸测量，以量化线粒体对 ATPmax 和活动障碍的贡献。这些特性相互作用：例如，自噬通量减少会促进氧化物质的积累损伤和去神经支配，理解这些关系将指导分析和解释此外，我们将使用无偏 RNA 测序 (RNA-seq) 来分析整个转录组。发现基因簇与体能丧失率个体差异之间的新关联（峰值 VO2)、肌肉质量和行动障碍的风险。位于维克森林和匹兹堡的实地中心，在招募和保留方面拥有出色的记录复杂研究中的老年人将招募 875 名 70-89 岁的女性和男性，步态速度 ≤ 1.0 m/s，提供足够的能力来识别个体和属性组合之间的重要关系以及行动不便的风险。 SOMMA 可以确定新疗法和定制锻炼方案的目标并确定优先顺序。还将创建一个独特的组织、血液档案，其中包含重要临床结果的纵向数据，科学界可以用来有效地测试关于肌肉和活动能力丧失的新假设老化。