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: 10641855
• 负责人: Benjamin Francis Miller
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641855
• 关键词: Acceleration; Acute; Address; Adult; Animals; Atrophic; Bed rest; Biochemical; Biology; CCI-779; Chronic; Chronic Disease; Contractile Proteins; Data; Deterioration; Disuse Atrophy; Elderly; Essential Amino Acids; FRAP1 gene; Failure; Fibrosis; Fractionation; Functional disorder; General Population; Goals; Growth; Hindlimb Suspension; Histology; Hospitalization; Human; Image; Impairment; Inbred BN Rats; Individual; Inpatients; Isotope Labeling; Kinetics; Knowledge; Length of Stay; Maintenance; Mitochondria; Mitochondrial Proteins; Modeling; Morphology; Muscle; Muscle function; Muscular Atrophy; Outcome; Procedures; Proteins; Proteomics; Rattus; Recording of previous events; Recovery; Recurrence; Resistance; Resolution; Signal Transduction; Sirolimus; Skeletal Muscle; Spirometry; Stress; Tail; Testing; Tissues; Tracer; Translating; Veterans; Work; age related; aged; comorbidity; critical period; disability; experimental study; frailty; functional outcomes; improved; innovation; juvenile animal; mRNA Translation; mTOR Inhibitor; mTOR inhibition; mechanotransduction; military veteran; mitochondrial dysfunction; muscle aging; muscle form; muscle strength; normal aging; novel; novel strategies; preservation; prevent; protein degradation; sarcopenia; secondary outcome; skeletal muscle wasting; transcriptome sequencing

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.

概括 与普通人群相比，老年退伍军人的合并症慢性疾病负担更高 在更频繁的住院住院治疗。经常住院和经常住院的结果是 与年龄相关的骨骼肌质量和力量丧失的加速（肌肉减少症）。的综合效果 肌肉减少症和住院治疗加剧了肌肉功能障碍，因为老年人无法充分恢复 从将它们放在加速轨迹上到失去独立性。因此，时期 在住院周围是一个关键时期，以防止残疾，失去独立性和脆弱性 退伍军人。目前尚不清楚为什么老年人的骨骼肌在萎缩一段时间后对再生具有抵抗力。 此外，当前增强骨骼肌再生的策略在很大程度上仍然无效。提议 工作很重要，因为它提供了证据表明MTOR激活是导致失败的原因，而不是解决方案 废弃后恢复肌肉。当前的提议具有创新性，因为它与当前的疗法有关 基于来自年轻动物的数据；它提出了三种独立但重叠的机制。然后 使用复杂的同位素标记和蛋白质组学方法来研究废弃的时期 萎缩。该提议的总体假设是，老年骨骼肌长期激活的mTOR 一段时间后，会损害肌肉质量/功能的恢复。为了检验这一总体假设，我们将使用 旧（28个月）f344/bn大鼠，有和没有mTOR抑制剂（雷帕霉素（Rapa））以解决三个特定目标 这确定是否抑制较老肌肉的慢性MTOR活性：1）纠正线粒体功能障碍 HU期间后，损害肌肉恢复 经过一段时间后，3）有助于解决纤维化，从而损害HU后肌肉恢复。我们的 假设是抑制长期活性MTOR活性的抑制作用将：1）增加选择性翻译 mRNA以改善线粒体蛋白重塑，改善网络连接的恶化和 提高线粒体功能，2）改善RE期间的蛋白质维护，3）减少肌肉纤维化 改善RE期间的机械转移。对于这些具体目标，我们将使用我们的创新针对性和 基于发现的动力学蛋白质组学以及新颖的（例如线粒体成像）和良好的 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 应该从根本上改变衰老肌肉废弃后增强恢复的方法。这个知识 可以帮助防止大量老年退伍军人的加速进展到残疾阈值。