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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

批准号：
10473096
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
项目类别：
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/10473096
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 Genetic Translation Goals 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 Resistance Resolution Signal Transduction Sirolimus Skeletal Muscle Stress Tail Testing Tissues Tracer Translating Veterans Work age related aged base comorbidity critical period disability experimental study frailty functional outcomes improved innovation juvenile animal 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

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