Role of Keratin 18 for Stress-induced Adaptive Strength Gains

角蛋白 18 在压力引起的适应性力量增益中的作用

基本信息

批准号：
10805876
负责人：
Cory W Baumann
金额：
$ 15.1万
依托单位：
OHIO UNIVERSITY ATHENS
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：
2023-09-30 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10805876
关键词：
Adult Age Binding Biological Assay C57BL/6 Mouse Caffeine Cell Nucleus Cell membrane Chronology Complex Coupling Cytoskeletal Modeling Data Development Dyes Dystrophin Elderly Exercise Exhibits Explosion Failure Female Filament Foundations Frail Elderly Future Genes Glycoproteins Heterogeneity Impairment Individual Intermediate Filament Proteins Intermediate Filaments Isometric Exercise Keratin Knockout Mice Link Location Measures Mediating Mediator Membrane Proteins Mus Muscle Muscle Weakness Muscular Atrophy Peripheral Phenotype Physiological Physiology Population Process Proteins Protocols documentation Publishing Risk Role Sarcomeres Skeletal Muscle Stress Testing Therapeutic exercise Torque Wild Type Mouse Work age related aged demographics exercise prescription frailty functional disability human data human old age (65+)in vivo longitudinal design male muscle aging muscle form muscle strength novel null mutation overexpression personalized medicine protein complex resilience resistance exercise response sarcopenia stressor therapeutic target uptake voltage

项目摘要

PROJECT SUMMARY Sarcopenia, loss of muscle strength and mass with age, is a major component of frailty. Muscle weakness appears to be critical as low strength is associated with more markers of frailty than chronological age. Geriatric and frail individuals are at greater risk of functional impairments due to an inability of skeletal muscle to adapt to physical stressors. Strength adaptations in response to physical stress or resistance training have been linked to loss of muscle quality, particularly excitation contraction (EC) coupling failure. Identifying mechanisms that counteract contraction-induced EC coupling failure and promote skeletal muscle adaptations are therefore essential to combating sarcopenia and frailty. Recent data suggest that keratin 18 (Krt18), an intermediate filament protein that associates with the dystrophin-glycoprotein complex, may be an important mediator of stress-induced adaptive strength gains that decreases with age. Specifically, we observed that the Krt18 gene was the most highly upregulated (7-fold) in muscle from young mice that gained strength after eccentric exercise. We also observed that increased expression of the Krt18 protein and strength gains were associated with increased expression of membrane-associated proteins. In muscle of old mice, expression of Krt18 was blunted and strength gains were dramatically lower when compared to young mice. Thus, our overarching hypothesis is that Krt18 facilitates skeletal muscle adaptation to exercise by increasing plasmalemmal stability to maintain EC coupling processes that become disrupted by repeated bouts of eccentric contractions. Ultimately, we posit Krt18 may play a role in increasing skeletal muscle resiliency and attenuating development and progression of sarcopenia and frailty. In Aim 1 we will determine if adaptive strength gains following repeated bouts of eccentric contractions are mediated by Krt18 in young mice by examining young (3-5-month-old) male and female wildtype (WT) and Krt18 knockout mice. In Aim 2 we will determine if age-related loss of Krt18 expression in muscle after repeated bouts of eccentric contractions is associated with blunted strength gains. To integrate age-related muscle adaptation (or lack thereof) with Krt18 expression, we will use young (3-5 months), adult (20-22 months) and old (27-29 months) male and female WT mice. All mice will perform repeated bouts of eccentric contractions in vivo and changes in isometric torque and plasmalemmal excitability will be tracked. Following the last contractile test, ex vivo physiology will be utilized to indirectly assess EC coupling failure. Markers of muscle damage will also be assessed and content of Krt18 and Krt18-intereacting proteins (e.g., dystrophin) will be measured. We predict that the ability of skeletal muscle remodel and adapt to repeated bouts of physical stress will correlate directly with the level of expression of Krt18, consistent with the idea, that the loss of Krt18 with age is an important mediator sarcopenia and frailty.

项目摘要肌肉减少症，肌肉力量的丧失和随着年龄的增长而质量，是脆弱的主要组成部分。肌肉无力似乎至关重要，因为低强度与年龄较大的脆弱标记有关。老年由于骨骼肌无法适应身体压力源。响应身体压力或抵抗训练的力量适应已连接肌肉质量的丧失，尤其是激发收缩（EC）耦合失败。确定该机制因此，应对收缩引起的EC耦合失败并促进骨骼肌适应对抗肌肉减少和脆弱的必不可少。最近的数据表明角蛋白18（KRT18），一种中级与肌营养不良蛋白 - 糖蛋白复合蛋白复合物相关的细丝蛋白可能是压力诱导的适应性强度随着年龄的增长而降低。具体而言，我们观察到KRT18基因是年轻小鼠的肌肉中最高度上调的（7倍），在偏心运动后获得了力量。我们还观察到，KRT18蛋白和强度增长的表达增加与膜相关蛋白的表达增加。在老鼠的肌肉中，KRT18的表达被钝化与年轻小鼠相比，力量的增长幅度大大降低。因此，我们的总体假设是 KRT18通过提高浆膜稳定性来促进骨骼肌适应运动以维持EC 耦合过程因偏心收缩的反复发作而破坏。最终，我们提出KRT18 可能在提高骨骼肌的弹性以及衰减的发展和发展方面发挥作用肌肉减少症和脆弱。在AIM 1中，我们将确定反复出现偏心次数后的自适应力量是否提高收缩是由KRT18在年轻小鼠中介导的，检查了年轻（3-5个月大）的男性和女性野生型（WT）和KRT18淘汰小鼠。在AIM 2中，我们将确定与年龄相关的KRT18在肌肉中的表达是否相关偏心收缩的反复发作与强度增长有关。集成与年龄有关的 KRT18表达的肌肉适应（或缺乏），我们将使用年轻（3-5个月），成人（20-22个月）和雄性和雌性WT小鼠的旧（27-29个月）。所有老鼠将进行重复的偏心收缩将跟踪体内和等距扭矩的变化和浆膜兴奋性。跟随最后一个收缩测试，离体生理学将用于间接评估EC耦合失败。肌肉的标记还将评估损伤，并将KRT18和KRT18切割蛋白（例如肌营养不良蛋白）的含量为测量。我们预测骨骼肌重塑并适应重复的身体压力的能力将与KRT18的表达水平直接相关，与这个想法一致，即Krt18随着年龄的增长而丧失是重要的调解人肌肉减少症和脆弱。