Muscle disuse and contractile dysfunction in the elderly

老年人的肌肉废用和收缩功能障碍

• 批准号: 7982727
• 负责人: MICHAEL J TOTH
• 金额: $ 39.76万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982727
• 关键词: Actins; Activities of Daily Living; Address; Affect; Biochemical; Buffers; Chronic; Clinical; Defect; Development; Educational Intervention; Elderly; Evaluation; Exercise; Fiber; Functional disorder; Human; Individual; Intervention; Kinetics; Knowledge; Laboratories; Length; Measurement; Mechanics; Microfilaments; Modification; Molecular; Muscle; Muscle Fibers; Muscle function; Myosin ATPase; Myosin Heavy Chains; Performance; Physical Capacity; Physiological; Physiological Adaptation; Population; Production; Property; Proteins; Rehabilitation therapy; Research; Skeletal Muscle; Structure; Testing; Thick; Thin Filament; Time; Training; case control; disability; experience; innovation; protein expression; public health relevance; translational study

DESCRIPTION (provided by applicant): Skeletal muscle disuse is an important contributing factor to physical disability. Disuse is more frequent in the elderly and they are more susceptible to its debilitating effects because of their diminished physiological reserve. Despite these facts, the mechanisms whereby disuse promotes skeletal muscle contractile dysfunction in this population remain largely undetermined. Therefore, we propose to systematically test for modifications of single muscle fiber structure and function that underlie contractile dysfunction. Elderly individuals characterized by chronic muscle disuse will be compared to carefully-matched controls with normal activity levels. Thereafter, elderly with chronic disuse will undergo an exercise intervention to remediate muscle disuse. We hypothesize that muscle disuse impairs contractile function, in part, through alterations in myosin kinetics, myofilament protein content and the mechanical properties of the myofilament lattice and that exercise rehabilitation will counteract these deficits. Aim 1 will examine the effect of disuse on mechanical, kinetic and structural properties and molecular composition of single muscle fibers in cases and controls. Aim 2 will investigate how increasing muscle use in elderly with chronic disuse via exercise training affects muscle fiber mechanical, kinetic and structural properties and molecular composition. Innovations in our laboratories have enabled assessment of muscle function at the level of the myosin-actin cross-bridge in humans for the first time. In combination with other mechanical, biochemical and anatomical measurements, these translational studies will provide the first comprehensive evaluation of the cellular and molecular mechanisms through which muscle disuse alters skeletal muscle structure and contractile function in elderly humans. This knowledge can assist in the development and refinement of preventative and corrective therapies for disability by tailoring these approaches to address specific molecular defects. PUBLIC HEALTH RELEVANCE: Skeletal muscle disuse is an important contributing factor to disability in the elderly. Despite the fact that elderly are more likely to experience disuse and lack the physiological reserve to buffer its detrimental effects, the cellular and molecular mechanisms that underlie disuse-related muscle contractile dysfunction remain largely unstudied. Knowledge gained from the proposed studies will assist in the development and refinement of preventative and corrective clinical therapies for disability by tailoring these approaches to address specific cellular and molecular defects.

描述（由申请人提供）：骨骼肌废用是导致身体残疾的重要因素。废用在老年人中更为常见，由于他们的生理储备减少，他们更容易受到其削弱作用的影响。尽管有这些事实，废用促进骨骼肌收缩功能障碍的机制在很大程度上仍然不确定。因此，我们建议系统地测试作为收缩功能障碍基础的单个肌纤维结构和功能的改变。将以慢性肌肉废用为特征的老年个体与具有正常活动水平的仔细匹配的对照进行比较。此后，患有慢性废用的老年人将接受运动干预，以修复肌肉废用。我们推测，肌肉废用损害收缩功能，在一定程度上，通过改变肌球蛋白动力学，肌丝蛋白含量和肌丝晶格的机械性能和运动康复将抵消这些赤字。目的1将研究废用对病例组和对照组单根肌纤维的力学、动力学和结构特性以及分子组成的影响。目的2将研究如何增加肌肉使用的老年人慢性废用通过运动训练影响肌纤维的机械，动力学和结构特性和分子组成。我们实验室的创新首次在人类肌球蛋白-肌动蛋白交叉桥水平上评估了肌肉功能。结合其他机械，生物化学和解剖学测量，这些转化研究将提供第一个全面的评估的细胞和分子机制，通过肌肉废用改变骨骼肌结构和收缩功能在老年人。这些知识可以通过定制这些方法来解决特定的分子缺陷，从而帮助开发和完善残疾的预防和矫正疗法。 公共卫生相关性：骨骼肌废用是老年人残疾的一个重要因素。尽管事实上，老年人更有可能经历废用，缺乏生理储备，以缓冲其不利影响，废用相关的肌肉收缩功能障碍的细胞和分子机制仍然在很大程度上未被研究。从拟议的研究中获得的知识将有助于通过定制这些方法来解决特定的细胞和分子缺陷，从而开发和完善残疾的预防和矫正临床疗法。