Day Nicholas J, Kelly Shane S, Lui Li-Yung, Mansfield Tyler A, Gaffrey Matthew J, Trejo Jesse B, Sagendorf Tyler J, Attah Kwame, Moore Ronald J, Douglas Collin M, Newman Anne B, Kritchevsky Stephen B, Kramer Philip A, Marcinek David J, Coen Paul M, Goodpaster Bret H, Hepple Russell T, Cawthon Peggy M, Petyuk Vladislav A, Esser Karyn A, Qian Wei-Jun, Cummings Steven R
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, California, USA.
medRxiv. 2023 Nov 8:2023.11.07.23298224. doi: 10.1101/2023.11.07.23298224.
Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (r = 0.48) between a higher oxidation level of 8 Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impair muscle power and strength, walking speed, and cardiopulmonary fitness with aging.
氧化应激被认为是衰老过程中肌肉功能和活动能力下降的一个因素；然而，其潜在的分子机制仍鲜有描述。我们推测，肌肉蛋白质上更高水平的半胱氨酸（Cys）氧化与活动能力的降低有关。在此，我们应用了一种新型的氧化还原蛋白质组学方法，来测量从56名受试者的外侧股四头肌活检样本中可逆的蛋白质Cys氧化情况，这些受试者来自肌肉、活动能力与衰老研究（SOMMA），这是一项基于社区的针对70岁及以上个体的队列研究。我们使用针对年龄、性别和体重进行调整的线性回归模型，测试了参与肌肉结构和收缩的关键肌肉蛋白质上的Cys氧化水平，是否与肌肉功能（腿部力量和强度）、步行速度以及健康状况（心肺运动测试中的VO峰值）相关。选定的伴肌动蛋白Cys位点的较高氧化水平与较低的VO峰值相关，而肌间蛋白-1、肌间蛋白-2和伴肌动蛋白Cys位点的较高氧化与较慢的步行速度相关。关键蛋白质如肌间蛋白-2、α-辅肌动蛋白-2和骨骼肌α-肌动蛋白中Cys位点的较高氧化与较低的腿部力量和强度相关。我们还观察到α-辅肌动蛋白-3中8个Cys位点的较高氧化水平与较强的腿部力量之间存在意外的相关性（r = 0.48）。尽管有这一观察结果，但总体结果支持这样的假设，即随着年龄增长，肌肉蛋白质的Cys氧化会损害肌肉力量、步行速度和心肺健康状况。
