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着增长。 与骨骼肌线粒体生物能下降有关，其后果包括 因此，身体机能、疲劳程度增加，并且更容易出现虚弱和残疾。 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。 初步数据表明，无机亚硝酸钠治疗可增强骨骼肌线粒体 久坐的老年人的生物能量学，它还提高了步行的代谢效率（即， 相同次最大步行活动的氧气利用率降低）这为 3- 提供了强有力的理由。 年试验更明确地分析亚硝酸钠治疗增强骨骼肌的效用 久坐的老年人的线粒体呼吸将作为方便的胶囊服用。 我们已经证明的新型制剂具有良好的耐受性并且与高血清亚硝酸盐水平相关。 目标 1 将强调线粒体生物能评估，包括离体 (Oroboros) 以及体内 体内（磷磁共振波谱）线粒体呼吸测量措施充分阐明 此外，骨骼肌 RNA 转录 (RNA-seq)、蛋白质印迹和 透射电子显微镜将进一步丰富有关亚硝酸盐对线粒体影响的见解 在目标 2 中，将包括补充血管分析以及血管流量测量。 （血流介导的扩张）和灌注（近红外光谱）以充分描绘亚硝酸盐的内皮效应。 目标 3 是探索性的，重点关注亚硝酸盐疗法对身体功能、日常活动和疲劳的影响。 身体机能通过生理测量（即峰值氧更新 (VO2) 和 次最大工作量时的摄氧量）和临床测量（即耐力 [70% 次最大工作量的耐受性 峰值摄氧量直至精疲力尽]、6 分钟步行距离、短体能电池和手柄 日常活动是通过加速度测量来测量的。 总体而言，该提案提供了一个以机械为导向的关键观点。 亚硝酸盐的功效；如果线粒体生物能量学在该分析中得到改善，未来的研究可以探索 亚硝酸盐可作为帮助克服老年久坐的疗法。