Mechanism through which chronically elevated mTOR activity impairs aged muscle recovery after disuse atrophy

长期升高的 mTOR 活性损害废用性萎缩后老年肌肉恢复的机制

基本信息

项目摘要

SUMMARY Older Veterans have a higher burden of comorbid chronic diseases compared to the general population, resulting in more frequent inpatient hospitalizations. A consequence of frequent and recurring hospitalizations is the acceleration of age-related loss of skeletal muscle mass and strength (sarcopenia). The combined effect of sarcopenia and hospitalization exacerbates muscle dysfunction since older adults do not adequately recover from bedrest placing them on an accelerated trajectory toward loss of independence. Therefore, the period around hospitalization is a critical period to intervene to prevent disability, loss of independence, and frailty in Veterans. It is not clear why skeletal muscle in older individuals is resistant to regrowth after a period of atrophy. Further, current strategies to enhance regrowth in older skeletal muscle remain largely ineffective. The proposed work is significant because it provides evidence that mTOR activation is the cause, not the solution, to the failure to recover muscle after disuse. The current proposal is innovative in that it goes against current therapies that were based on data from young animals; it proposes three independent but overlapping mechanisms; and it uses sophisticated combined isotope labeling and proteomic approaches to study the periods around disuse atrophy. The overall hypothesis of this proposal is that that chronically activated mTOR in aged skeletal muscle impairs the recovery of muscle mass/function after a period of disuse. To test this overall hypothesis, we will use old (28 mo) F344/BN rats with and without an mTOR inhibitor (rapamycin (Rapa)) to address three specific aims that determine if inhibiting chronic mTOR activity in older muscle: 1) corrects the mitochondrial dysfunction that impairs muscle recovery after a period of HU, 2) improves the proteostatic stress that impairs muscle recovery after a period of HU, and 3) helps resolve fibrosis that impairs muscle recovery after a period of HU. Our hypotheses are that suppression of chronically active mTOR activity will: 1) increase the selective translation of mRNA to improve mitochondrial protein remodeling, improve the deterioration of network connectivity, and improve mitochondrial function, 2) improve proteostatic maintenance during RE, and 3) reduce muscle fibrosis to improve mechanotransduction during RE. For these specific aims we will use our innovative targeted and discovery-based kinetic proteomics along with novel (e.g. mitochondrial imaging) and well-established secondary outcomes, including functional outcomes, to support our proteomic outcomes. It is hoped that these experiments will clarify the underlying cause of failed recovery in muscle of older Veterans, and whether we should fundamentally change the approach to enhance recovery after disuse in aged muscle. This knowledge could help prevent the accelerated progression to a disability threshold for a significant number of older Veterans.
总结 与普通人群相比,老年退伍军人有更高的共病慢性疾病负担, 更频繁的住院治疗频繁和反复住院的后果是, 加速与年龄相关的骨骼肌质量和力量的损失(肌肉减少症)。的共同作用 肌肉减少症和住院会加剧肌肉功能障碍,因为老年人不能充分恢复 从卧床休息开始,使他们加速失去独立性。因此, 住院前后是进行干预以防止残疾、丧失独立性和身体虚弱的关键时期。 老兵目前尚不清楚为什么老年人的骨骼肌在萎缩一段时间后会抵抗再生。 此外,目前的策略,以提高再生在老年骨骼肌仍然在很大程度上无效。拟议 这项工作意义重大,因为它提供了mTOR激活是失败原因而不是解决方案的证据 使肌肉在废用后恢复。目前的建议是创新的,因为它违背了目前的疗法, 基于年轻动物的数据;它提出了三个独立但重叠的机制;它 使用复杂的同位素标记和蛋白质组学方法来研究废弃前后的时期 萎缩这项提议的总体假设是,老年骨骼肌中慢性激活的mTOR 在废用一段时间后损害肌肉质量/功能的恢复。为了验证这个假设,我们将使用 使用和不使用mTOR抑制剂(雷帕霉素(Rapa))的老年(28个月)F344/BN大鼠,以解决三个特定目标 确定是否抑制老年肌肉中的慢性mTOR活性:1)纠正线粒体功能障碍, 在一段HU后损害肌肉恢复,2)改善损害肌肉恢复的蛋白质抑制应激 3)有助于解决纤维化,纤维化在HU一段时间后损害肌肉恢复。我们 假设慢性活性mTOR活性抑制将:1)增加 mRNA改善线粒体蛋白质重塑,改善网络连接的恶化, 改善线粒体功能,2)改善RE期间蛋白质稳定维持,和3)减少肌肉纤维化 以改善RE期间的机械传导。对于这些具体目标,我们将使用我们的创新,有针对性和 基于发现的动力学蛋白质组学沿着新的(例如线粒体成像)和完善的 次要结果,包括功能结果,以支持我们的蛋白质组学结果。希望这些 实验将阐明老年退伍军人肌肉恢复失败的根本原因,以及我们是否 应该从根本上改变方法,以提高恢复后废用在老年肌肉。这些知识 这可能有助于防止大量老年退伍军人加速发展到残疾门槛。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Benjamin Francis Miller其他文献

Benjamin Francis Miller的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Benjamin Francis Miller', 18)}}的其他基金

Mechanism through which chronically elevated mTOR activity impairs aged muscle recovery after disuse atrophy
长期升高的 mTOR 活性损害废用性萎缩后老年肌肉恢复的机制
  • 批准号:
    10473096
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Determining the context specificity of metformin treatment on muscle mitochondria and healthspan
确定二甲双胍治疗对肌肉线粒体和健康寿命的背景特异性
  • 批准号:
    10462944
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Dissecting the integrated mechanisms of protein turnover to prevent proteostatic decline with aging
剖析蛋白质周转的综合机制,以防止蛋白质沉积随衰老而下降
  • 批准号:
    10706458
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Dissecting the integrated mechanisms of protein turnover to prevent proteostatic decline with aging
剖析蛋白质周转的综合机制,以防止蛋白质沉积随衰老而下降
  • 批准号:
    10390925
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Determining the context specificity of metformin treatment on muscle mitochondria and healthspan
确定二甲双胍治疗对肌肉线粒体和健康寿命的背景特异性
  • 批准号:
    10596174
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
DNA turnover in myofibers is an unrecognized mechanism for maintaining skeletal muscle health
肌纤维中的 DNA 更新是维持骨骼肌健康的一种未被认识的机制
  • 批准号:
    10239252
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
A novel approach to understand a mechanism of proteostatic decline with aging
一种理解衰老过程中蛋白质抑制下降机制的新方法
  • 批准号:
    10229298
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
DNA turnover in myofibers is an unrecognized mechanism for maintaining skeletal muscle health
肌纤维中的 DNA 更新是维持骨骼肌健康的一种未被认识的机制
  • 批准号:
    10065144
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Does insulin sensitivity impact the potential of metformin to slow aging?
胰岛素敏感性是否会影响二甲双胍延缓衰老的潜力?
  • 批准号:
    10579890
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Does insulin sensitivity impact the potential of metformin to slow aging?
胰岛素敏感性是否会影响二甲双胍延缓衰老的潜力?
  • 批准号:
    9999395
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了