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

项目总结 尽管很大一部分美国人口年龄较大、超重、肥胖或生活在 涉及脂肪组织在肌肉中沉积的增加，对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，贫乏的武力和权力 肥胖或老年人的单个肌肉纤维和整个肌肉可以产生和传播。 由于肌肉中更多的脂肪渗透而导致的后遗症的潜在负面后果包括虚弱， 久坐行为的风险增加，代谢异常加速，活动能力普遍丧失， 独立。在这个整合和翻译的项目中，我们将比较肌肉力量和力量，以及 膝关节伸肌中脂肪组织的数量和分布，从分子水平到整个肌肉水平 健康、久坐的肌肉：年轻(25-45岁)低脂肪、年轻高脂肪和老年(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)和波谱(MRS) 这些技术将被用来量化整个肌肉脂肪沉积的关键方面及其对肌肉的影响 活生生的建筑。我们还将量化脂肪组织对单个肌肉纤维功能和 研究10名(男性5名，女性5名)青少年肌肉功能障碍的潜在分子机制 将接受股外侧肌活组织检查的低脂肪、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量和功率速度关系，如 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的渗透和/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和弥散张量MRI量化肌肉的数量、位置和影响 脂肪沉积的纤维轨迹。我们还将测量整个肌肉和单个肌肉中的肌内脂肪含量 纤维，分别用~1H MRS和油红-O免疫组织化学染色。在目标3中，我们将评估 肌肉中脂肪组织沉积导致的结构紊乱与较低的整体率有关。 肌肉比力和力量，从而提供了脂肪渗透的病理后果的证据 除此之外，健康的年轻人和老年人。该项目的成果将：1)开发关键的新信息 这将解决这一未被研究的研究领域的重大知识差距，2)提供原始数据 用来提出新的假设和改进我们对与脂肪相关的重要问题的处理方法 年轻人和老年人的肌肉功能障碍，以及3)建立了一条独特的翻译调查路线 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， 构成一个具有迅速产生变革性新知识的潜力的创新项目。AS 许多疾病和紊乱，以及衰老，都与肌肉中脂肪沉积增加有关。 在纸巾方面，该项目有可能造福于相当一部分美国人口的健康。

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.