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Protein modification and the aging phenotype of human skeletal muscle

蛋白质修饰与人类骨骼肌的衰老表型

基本信息

批准号：
10593791
负责人：
Damien Mark Callahan
金额：
$ 18.49万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593791
关键词：
Actins Acute Address Adult Age Aging Area Atrophic Binding Biology Cardiac Cell Respiration Characteristics Clinical Coupling Cyclic AMP-Dependent Protein Kinases Data Dependence Elderly Exhibits Failure Fatigue Fiber Functional disorder Goals Heart Heart failure Human Impairment In Vitro Intervention Isometric Contraction Isometric Exercise Kinetics Lead Life Longevity Mediating Modification Molecular Molecular Target Muscle Muscle Cells Muscle Fibers Muscle Tension Muscle function Muscular Atrophy Myocardial Myosin ATPase Myosin Regulatory Light Chains Outcome Performance Phenotype Phosphorylation Physical Function Physical Rehabilitation Post-Translational Protein Processing Protein Dephosphorylation Protein Isoforms Proteins Rehabilitation Outcome Reporting Research Resistance Risk Role Sarcomeres Sequence Homology Skeletal Muscle Testing Thick Filament Thin Filament Tissue Sample Tissues Translating Walking age related disability experience experimental study fall risk frailty genetic regulatory protein improved in vivo interest muscle aging muscle form myosin-binding protein C novel physically handicapped pre-clinical preclinical study sarcopenia screening skeletal skeletal muscle wasting young adult

项目摘要

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.

项目摘要与年龄相关的肌肉收缩性能下降是由肌肉尺寸减少（萎缩）介导的以及肌动蛋白-肌球蛋白跨桥功能的改变，其与大小无关。它们共同促成了肌肉减少症，即与年龄相关的骨骼肌质量和功能丧失。肌肉减少症的一个标志是收缩力（=力和速度的乘积），这反过来又预示着身体功能障碍和运动能力残疾。重要的是，收缩力在生命的早期下降，并且比心脏收缩力的下降更急剧。收缩力或肌肉大小，从而表明功率受到独特的影响，机制等在高速度的重复收缩过程中，肌肉疲劳性也随着年龄的增长而增加，老年人，健康的成年人经历了更大的减少肌肉力量的过程中，一次反复的自主收缩结合起来，肌肉老化的这些方面使老年人成年人在重复性活动（爬楼梯、步行等）中发生福尔斯和身体损伤的风险更大。有些矛盾的是，肌肉张力（每单位横截面积的力）已被证明增加随着年龄的增长，收缩速度为零（等距）。同样，老年人在工作期间也不容易疲劳。等长收缩这种对功能特征知之甚少的星座定义了一种衰老，骨骼肌的表型，其机制可能揭示干预改善的重要靶点老年肌肉减少症患者的身体功能。我们建议，在跨桥水平生物学的改变，老化肌节导致速度依赖性收缩功能障碍，肌节蛋白肌球蛋白结合蛋白C（MyBP-C）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，已知可调节心肌细胞的生长，通过磷酸化依赖的相互作用与细和粗丝的收缩性。虽然骨瘦如柴， MyBP-C的心脏亚型是高度保守的，具有结构和序列同源性， MyBP-C是否对骨骼肌收缩性具有类似的磷酸化依赖性影响。最近临床前研究表明骨骼肌MyBP-C磷酸化影响收缩力和速度，和疲劳收缩改变磷酸化差异。我们在离体人单个肌肉中的研究纤维将把临床前的证据翻译给人类，使我们能够询问MyBP-C对年龄的影响。和骨骼肌收缩力的疲劳相关变化。我们将鉴定翻译后修饰，在筛选人体内其他感兴趣的候选者时，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基础数据，支持追求分子靶点，以改善老年人的临床结果为目标的干预措施。