Nitrite therapy to improve mitochondrial energetics and physical activity in older adults

亚硝酸盐疗法可改善老年人的线粒体能量和身体活动

• 批准号: 10250301
• 负责人: Daniel E. Forman
• 金额: $ 64.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250301
• 关键词: Accelerometer; Adenosine Triphosphate; Adult; Age; Bioenergetics; Biopsy; Blood Platelets; Blood Vessels; Chronic; Clinical; Data; Deacetylase; Distal; Elderly; Endothelium; Equilibrium; Exercise; Foundations; Future; Genetic Transcription; Genus Hippocampus; Growth; Health; Hypoxia; Intervention; Link; Lysine; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolic; Mission; Mitochondria; Molecular; Morphology; Muscle; Muscle Mitochondria; National Institute on Aging; Near-Infrared Spectroscopy; Nicotinamide adenine dinucleotide; Nitrites; Older Population; Oxygen; Oxygen Consumption; Pattern; Performance; Perfusion; Personal Satisfaction; Phosphorus; Physical Function; Physical Performance; Physical activity; Physiological; Physiology; Placebos; Population; Preparation; Production; Publishing; Quality of life; RNA; Randomized Controlled Trials; Resistance; Resolution; Respiration; Salts; Seminal; Serum; Sirtuins; Site; Skeletal Muscle; Sodium Nitrite; Structure; Testing; Therapeutic; Transmission Electron Microscopy; Ultrasonography; Update; Vascular Endothelium; Vasodilation; Walking; Western Blotting; Work; Workload; age related; capsule; cardiorespiratory fitness; disability; endurance exercise; exercise intolerance; exercise training; exhaustion; fitness; frailty; human old age (65+); improved; in vivo; indexing; insight; mitochondrial metabolism; multidisciplinary; novel; prevent; primary outcome; sedentary; tissue oxygenation; transcriptome sequencing

Contemporary demographic patterns include the prominent growth of the older adult population. Old age is associated with declining skeletal muscle mitochondrial bioenergetics, and ramifications include decreased physical function, increased fatigability, and greater vulnerability to frailty and disability. Therefore, augmenting mitochondrial respiration may help to fundamentally improve the health and wellbeing of older adults. Our preliminary data show that inorganic sodium nitrite treatment augments skeletal muscle mitochondrial bioenergetics in older sedentary adults and that it also enhances the metabolic efficiency of walking (i.e., reduced oxygen utilization for the same submaximal walking activity). This provides strong rationale for a 3- year trial to more definitively analyze the utility of sodium nitrite treatment to enhance skeletal muscle mitochondrial respiration in older sedentary adults. Nitrites will be administered as convenient capsules, a novel preparation that we have demonstrated is well-tolerated and associated with high serum nitrite levels. Aim 1 will emphasize mitochondrial bioenergetic assessments, and include ex vivo (Oroboros) as well as in vivo (phosphorus magnetic resonance spectroscopy) mitochondrial respirometry measures to fully elucidate pertinent physiology. Furthermore, skeletal muscle RNA transcription (RNA-seq), Western blots, and transmission electron microscopy will additional enrich insights regarding nitrite effects on mitochondrial performance. In Aim 2, complementary vascular analyses will be included, with measures of vascular flow (flow-mediated dilation) and perfusion (near infrared spectroscopy) to fully delineate nitrite’s endothelial effects. Aim 3 is exploratory, and focuses on nitrite therapy’s impact on physical function, daily activity, and fatigability. Physical function is assessed both in terms of physiological measures (i.e., peak oxygen update (VO2) and VO2 at a submaximal workload) and clinical measures (i.e., endurance [tolerance of submaximal work at 70% peak VO2 until exhaustion], 6 minute walk distance, the Short Physical Performance Battery, and handgrip strength). Daily activity is measured using accelerometry. Fatigability is measured in respect to perceived and performance indices. Overall, this proposal provides a critical mechanistically-oriented perspective regarding the efficacy of nitrite; if mitochondrial bioenergetics are improved in this analysis, future studies can explore nitrite’s utility as a therapy to help surmount sedentariness in old age.

当代人口模式包括老年人口的显著增长。老年是 与骨骼肌线粒体生物能量学下降有关，其后果包括 身体功能，增加疲劳，更容易虚弱和残疾。因此，增强 线粒体呼吸可能有助于从根本上改善老年人的健康和福祉。我们 初步数据显示，无机亚硝酸钠处理增加骨骼肌线粒体 并且它还增强了步行的代谢效率（即， 对于相同的次最大步行活动减少的氧利用）。这为3- 一项为期一年的试验，以更明确地分析亚硝酸钠治疗对增强骨骼肌的效用 线粒体呼吸在老年久坐的成年人。亚硝酸盐将作为方便的胶囊给药， 我们已经证明的新制剂耐受性良好，并与高血清亚硝酸盐水平相关。 目的1将强调线粒体生物能量评估，包括离体（Oroboros）以及在 体内（磷磁共振光谱）线粒体呼吸测量，以充分阐明 相关生理学此外，骨骼肌RNA转录（RNA-seq），蛋白质印迹， 透射电子显微镜将进一步丰富有关亚硝酸盐对线粒体的影响的见解 性能在目标2中，将纳入补充血管分析，并测量血管流量 （流动介导的扩张）和灌注（近红外光谱）来充分描绘亚硝酸盐的内皮效应。 目的3是探索性的，重点是亚硝酸盐治疗对身体功能，日常活动和疲劳的影响。 根据生理测量（即，峰值氧更新（VO 2）和 次最大工作负荷时的VO 2）和临床测量（即，耐力〔70%次极量工作的耐力 峰值VO 2直到耗尽]、6分钟步行距离、短体力功能成套测验和握力 强度）。日常活动是用加速度计测量的。可吸收性是根据感知和 性能指标总的来说，该提案提供了一个关键的机械导向的角度， 亚硝酸盐的功效;如果线粒体生物能量学在这项分析中得到改善，未来的研究可以探索 亚硝酸盐的效用作为一种疗法，以帮助克服久坐不动的老年人。