Mechanical Disruption of Force Transmission by Adipose Tissue in Human Skeletal Muscle

人体骨骼肌脂肪组织力传递的机械破坏

• 批准号: 9751770
• 负责人: JANE A KENT
• 金额: $ 16.94万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751770
• 关键词: Actins; Address; Adipocytes; Adipose tissue; Adult; Advisory Committees; Age; Aging; Anatomy; Applications Grants; Architecture; Area; Attention; Biochemical; Biopsy; Biopsy Specimen; Blood Vessels; Body mass index; Cells; Characteristics; Cross-Sectional Studies; Data; Data Set; Deposition; Diabetes Mellitus; Diffusion; Disease; Elderly; Extensor; Fascicle; Fatty acid glycerol esters; Fiber; Fibroblasts; Functional disorder; Future; Geometry; Goals; Greater curvature of stomach; Health; Health Benefit; Heart failure; Histocytochemistry; Human; Impairment; In Vitro; Individual; Infiltration; Intramuscular; Investigation; Kinetics; Knee; Knowledge; Length; Lipids; Location; Magnetic Resonance Imaging; Measures; Mechanics; Metabolic; Methods; Microfilaments; Mission; Molecular; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscular Dystrophies; Myosin ATPase; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Obesity; Oils; Older Population; Organ; Overweight; Participant; Pathologic; Pathology; Physical Function; Physical activity; Population; Populations at Risk; Preparation; Prevalence; Production; Research; Research Design; Risk; Skeletal Muscle; Spectrum Analysis; Structure; Techniques; Testing; Tissues; United States National Institutes of Health; Weight; Woman; base; cell type; design; experience; follow-up; imaging modality; in vivo; innovation; men; muscle strength; muscular structure; novel; older men; older women; quadriceps muscle; recruit; relating to nervous system; sedentary; sedentary lifestyle; sex; spectroscopic imaging; transmission process; vastus lateralis; young adult; young man

PROJECT SUMMARY Although significant portions of the US population are older, overweight, obese, or living with conditions that involve increased deposition of adipose tissue in muscle, little is known about the potential mechanical effects of fat deposition on skeletal muscle function. Emerging evidence suggests that poor force and power production and transmission can occur in single muscle fibers and whole muscle in obese or older individuals. The potential negative consequences of the sequelae due to greater fat infiltration in muscle include weakness, increased risks for sedentary behavior, accelerated metabolic abnormalities and a general loss of mobility and independence. In this integrative and translational project, we will compare muscle force and power, and the amount and distribution of adipose tissue, from the molecular to whole-muscle level in the knee extensor muscles of healthy, sedentary: young (25-45 yr) low-fat, young high-fat, and older (65-75 yr) high-fat adults (8 men, 8 women per group). Noninvasive magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques will be used to quantify key aspects of whole-muscle fat deposition and its effects on muscle architecture in vivo. We will also quantify the effects of adipose tissue on single muscle fiber function and address the potential molecular mechanisms of muscle dysfunction in subsets of 10 (5 men, 5 women) young low-fat, young high-fat and older high-fat adults who will undergo vastus lateralis muscle biopsies. In Aim 1, we will compare whole-muscle and single-fiber force- and power-velocity relationships in our study groups, as well as myofilament mechanics and myosin-actin cross-bridge kinetics, to quantify the extent to which these fundamental characteristics of muscle are altered with fat infiltration and/or older age. In Aim 2, we will use T1-weighted, 6-point Dixon, and diffusion tensor MRI to quantify the amount, location and effects on muscle fiber tracks of fat deposits. We will also measure intramyocellular lipid content in whole muscle and single fibers, using 1H MRS and oil red-O immuno-histochemistry, respectively. In Aim 3, we will evaluate whether the architectural disruptions due to adipose tissue deposition in muscle are associated with lower whole- muscle specific force and power, thus providing evidence of the pathological consequences of fat infiltration in otherwise healthy young and older adults. The results of this project will 1) develop critical new information that will address a significant knowledge gap in this understudied area of research, 2) provide original data to be used to formulate novel hypotheses and refine our approach to the important question of adipose-related muscle dysfunction in young and old, and 3) establish a unique translational line of investigation by an experienced research team. These objectives are highly relevant to the missions of NIH, NIAMS and NIA, and constitute an innovative project with the potential for rapidly generating transformative new knowledge. As numerous diseases and disorders, as well as aging, are associated with increased fat deposition in muscle tissue, the project has the potential to benefit the health of a significant portion of the U.S. population.

项目摘要 尽管美国大部分人口的年龄较大，但超重，肥胖或生活条件 涉及增加脂肪组织在肌肉中的沉积，对潜在的机械效应知之甚少 骨骼肌功能上的脂肪沉积。新兴的证据表明，力量和力量差 在肥胖或年龄较大的个体中，单个肌肉纤维和整个肌肉可能发生生产和传播。 后遗症引起的潜在负面后果，肌肉中的脂肪渗透更多，包括无力， 增加久坐行为，加速代谢异常以及总体流动性和一般丧失和的风险增加 独立。在这个综合和翻译项目中，我们将比较肌肉力量和力量，以及 脂肪组织的数量和分布，从膝盖伸肌的分子到全肌水平 健康，久坐的肌肉：年轻（25-45年）低脂，年轻高脂和年龄较大（65-75岁）高脂成年人（8岁 男性，每组8个女性）。无创磁共振成像（MRI）和光谱法（MRS） 技术将用于量化全肌肉脂肪沉积的关键方面及其对肌肉的影响 体内建筑。我们还将量化脂肪组织对单肌纤维功能的影响和 解决10（5名男性，5名女性）子集中肌肉功能障碍的潜在分子机制 低脂，年轻的高脂和年长的高脂成年人，他们将进行巨大的外侧肌肉活检。在AIM 1中， 我们将比较研究小组中的全肌和单纤维力和电源关系，作为 以及肌膜力学和肌球蛋白 - 肌动蛋白跨桥动力学，以量化这些程度 肌肉的基本特征会随着脂肪浸润和/或年龄的增长而改变。在AIM 2中，我们将使用 T1加权，6点Dixon和扩散张量MRI，以量化肌肉的数量，位置和影响 脂肪沉积的纤维轨道。我们还将测量整个肌肉和单个肌肉中细胞内脂质含量 纤维分别使用1H MRS和油红色IMO免疫 - 归化学。在AIM 3中，我们将评估是否 肌肉中脂肪组织沉积引起的建筑破坏与较低的整体相关 肌肉特异性力和力量，因此提供了脂肪浸润的病理后果的证据 否则健康的年轻和老年人。该项目的结果将1）开发关键的新信息 这将解决研究不足的研究领域的显着知识差距，2）提供原始数据 用于制定新的假设并完善我们对脂肪相关的重要问题的方法 年轻人和老年人的肌肉功能障碍，以及3）建立一个独特的翻译调查线 经验丰富的研究团队。这些目标与NIH，NIAMS和NIA的任务高度相关，以及 构成一个创新的项目，具有快速产生变革性新知识的潜力。作为 许多疾病和疾病以及衰老都与肌肉脂肪沉积增加有关 组织，该项目有可能使大部分美国人口的健康受益。