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.

项目概要 尽管美国人口中有很大一部分年龄较大、超重、肥胖或生活条件 涉及肌肉中脂肪组织沉积的增加，但对其潜在的机械效应知之甚少 脂肪沉积对骨骼肌功能的影响。新出现的证据表明，武力和权力不足 肥胖或老年人的单肌纤维和整个肌肉中都会产生和传播。 由于肌肉中脂肪浸润较多，后遗症的潜在负面后果包括虚弱、 久坐行为、加速代谢异常和普遍丧失活动能力的风险增加 独立。在这个综合性和转化性项目中，我们将比较肌肉力量和力量，以及 膝伸肌中从分子水平到整个肌肉水平的脂肪组织的数量和分布 健康、久坐的肌肉：年轻（25-45 岁）低脂肪、年轻高脂肪和老年人（65-75 岁）高脂肪成年人（8 男性，每组 8 名女性）。无创磁共振成像 (MRI) 和光谱学 (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 体内的建筑。我们还将量化脂肪组织对单肌纤维功能的影响和 解决 10 名（5 名男性，5 名女性）年轻人中肌肉功能障碍的潜在分子机制 将接受股外侧肌活检的低脂肪、年轻高脂肪和老年高脂肪成年人。在目标 1 中， 我们将在我们的研究组中比较全肌肉和单纤维的力和功率速度关系，如下所示 以及肌丝力学和肌球蛋白-肌动蛋白跨桥动力学，以量化这些 肌肉的基本特征会随着脂肪渗透和/或年龄的增长而改变。在目标 2 中，我们将使用 T1 加权、6 点 Dixon 和扩散张量 MRI，可量化肌肉的数量、位置和影响 脂肪沉积物的纤维轨迹。我们还将测量整个肌肉和单个肌肉的肌细胞内脂质含量 纤维，分别使用 1H MRS 和油红-O 免疫组织化学。在目标 3 中，我们将评估是否 由于肌肉中脂肪组织沉积而导致的结构破坏与较低的整体性有关。 肌肉比力和功率，从而提供脂肪浸润病理后果的证据 其他方面健康的年轻人和老年人。该项目的结果将 1) 开发关键的新信息 这将解决该研究领域的重大知识差距，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重要问题的方法 年轻人和老年人的肌肉功能障碍，以及 3) 通过 经验丰富的研究团队。这些目标与 NIH、NIAMS 和 NIA 的使命高度相关，并且 构成一个具有快速产生变革性新知识潜力的创新项目。作为 许多疾病和病症以及衰老都与肌肉中脂肪沉积增加有关 组织，该项目有可能使很大一部分美国人口的健康受益。