Muscle disuse and contractile dysfunction in the elderly

描述（由申请人提供）：骨骼肌失用是导致身体残疾的重要因素。老年人停用药物的情况更为频繁，由于他们的生理储备减少，他们更容易受到药物的影响。尽管有这些事实，在这个人群中，废弃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导致收缩功能障碍的单个肌纤维结构和功能的改变。以慢性肌肉失用为特征的老年人将与正常活动水平的精心匹配的对照进行比较。此后，老年慢性失用将进行运动干预，以修复肌肉失用。我们假设肌肉废用损害收缩功能，部分是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特性，而运动康复将抵消这些缺陷。目的1将在病例和对照中检查废弃对单个肌肉纤维的机械，动力学和结构特性以及分子组成的影响。目的2将研究通过运动训练增加老年慢性失用患者的肌肉使用如何影响肌纤维的力学、动力学和结构特性以及分子组成。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肌肉功能。结合其他机械、生化和解剖学测量，这些转化研究将首次全面评估肌肉废用改变老年人骨骼肌结构和收缩功能的细胞和分子机制。这些知识可以通过定制这些方法来解决特定的分子缺陷，从而帮助残疾的预防性和纠正性治疗的发展和完善。

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.