Protein modification and the aging phenotype of human skeletal muscle

项目摘要 与年龄相关的肌肉收缩性能的降低是通过肌肉尺寸的缩小(萎缩)来调节的 肌动蛋白-肌球蛋白跨桥功能的改变与大小无关。他们共同致力于 骨质疏松症，与年龄相关的骨骼肌质量和功能的丧失。骨质疏松症的一个特点是 收缩力量(=力和速度的乘积)，它反过来又预示着身体机能障碍和活动能力 残疾。重要的是，在人的一生中，收缩能力下降得更早，而且比生命中 收缩力量或肌肉大小，从而表明力量受到独特的 机械装置。在反复的高速收缩中，肌肉的疲劳性也会随着年龄的增长而增加，例如 年长的、健康的成年人在一段时间内肌肉力量的下降幅度会更大 一次重复的自愿宫缩。结合起来，肌肉老化的这些方面会让人变老 成年人在重复活动(爬楼梯、步行等)时摔倒和身体损伤的风险更大。 有些自相矛盾的是，肌肉张力(单位横截面积的力量)已经显示出增加 收缩速度为零时的年龄(等轴测)。同样，老年人也不那么容易疲劳。 等长收缩。这一系列鲜为人知的功能特征定义了衰老 骨骼肌表型及其机制可能揭示改善干预的重要靶点 老年石棺减少症患者的身体功能。我们提出了跨桥水平生物学的改变 老化的肌节有助于速度依赖性收缩功能障碍，并将在 人类骨骼肌检验肌球蛋白结合蛋白C(MyBP-C)的假说 是这一现象的核心。 MyBP-C是一种位于肌节中心附近的调节蛋白，已知可调节心肌 通过依赖磷酸化与细丝和粗丝的相互作用来收缩。而骨骼和 MyBP-C的心脏亚型高度保守，具有结构和序列同源性，目前尚不清楚 MyBP-C是否具有类似的磷酸化依赖对骨骼肌收缩能力的影响。近期 临床前研究表明，骨骼MyBP-C的磷酸化影响收缩力和速度，以及年龄 疲劳性收缩会不同地改变磷酸化。我们对分离的人单肌的研究 纤维将把临床前的证据转化为人类，并使我们能够询问MyBP-C对年龄的影响 以及与疲劳相关的骨骼肌收缩能力的变化。我们将确定翻译后的修改 肌瘤蛋白与年龄和疲劳的关系，同时筛选人类内其他感兴趣的候选蛋白 肌肉细胞。这些研究将揭示关于鲜为人知的衰老表型的重要信息 同时建立支持追求分子靶标的基础数据 旨在改善老年人临床结果的干预措施。

Project Summary Age-related reductions in muscle contractile performance are mediated by reductions in muscle size (atrophy) and alterations in actin-myosin cross bridge function that are independent of size. Together, they contribute to sarcopenia, the age-related loss of skeletal muscle mass and function. A hallmark of sarcopenia is the loss of contractile power (= product of force and velocity) which, in turn, predicts physical dysfunction, and mobility disability. Importantly, contractile power declines earlier in life and more precipitously than reductions in contractile force or muscle size, thereby suggesting that power is subject to the influence of unique mechanisms. During repeated contractions of high velocity, muscle fatigability is also increased with age, such that older, healthy adults experience a much greater reduction in muscular power over the course of a single bout of repeated voluntary contractions. In combination, these aspects of muscle aging leave older adults at greater risk of falls and physical impairments during repetitious activities (stair climbing, walking etc.). Somewhat paradoxically, muscle tension (force per unit cross sectional area) has been shown to increase with age when contractile velocity is zero (isometric). Similarly, older adults are less fatigable during isometric contractions. This constellation of poorly understood functional characteristics defines an Aging Phenotype of skeletal muscle whose mechanisms may reveal important targets for intervention for improving physical function in older adults with sarcopenia. We propose that alterations in cross-bridge level biology in the aging sarcomere contribute to velocity-dependent contractile dysfunction and will perform experiments in human skeletal muscle to test the hypothesis that the sarcomeric protein Myosin Binding Protein C (MyBP-C) is central to this phenomenon. MyBP-C is a regulatory protein located near the center of the sarcomere, known to modulate myocardial contractility via phosphorylation-dependent interactions with the thin and thick filaments. While skeletal and cardiac isoforms of MyBP-C are highly conserved and share structural and sequence homology, it is not clear whether MyBP-C has similar phosphorylation-dependent influences on skeletal muscle contractility. Recent pre-clinical studies suggest skeletal MyBP-C phosphorylation influences contractile force and velocity, and age and fatiguing contractions alter phosphorylation differentially. Our studies in isolated human single muscle fibers will translate pre-clinical evidence to humans and allow us to interrogate the influence of MyBP-C on age and fatigue-related changes in skeletal muscle contractility. We will identify post translational modifications to sarcomeric proteins with age and fatigue while screening for other candidates of interest within the human muscle cell. These studies will reveal important information regarding the poorly understood Aging Phenotype of Skeletal Muscle while establishing foundational data supporting the pursuit of molecular targets for interventions with the goal of improving clinical outcomes in older adults.