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

当代人口模式包括老年人口的显著增长。年老就是 与骨骼肌线粒体生物能量学下降有关，其后果包括 身体机能，疲劳性增加，更容易虚弱和残疾。因此，增加 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。我们的 初步数据显示，无机亚硝酸钠治疗增加了骨骼肌线粒体 生物能量学在久坐不动的老年人中的作用，它还提高了步行的新陈代谢效率(即， 减少了相同次最大步行活动的氧气利用率)。这为3- 一年的试验，以更明确地分析亚硝酸钠治疗增强骨骼肌的效用 久坐不动的老年人的线粒体呼吸。亚硝酸盐将作为方便胶囊服用，一种 我们已经证明的新制剂具有良好的耐受性，并与高血清亚硝酸盐水平有关。 目标1将强调线粒体生物能量评估，包括体外(Oroboros)以及 VIVO(磷磁共振波谱)线粒体呼吸测量方法充分阐明 中肯的生理学。此外，骨骼肌RNA转录(RNA-seq)、Western blots和 透射电子显微镜将进一步丰富对亚硝酸盐对线粒体影响的深入了解 性能。在目标2中，将包括补充的血管分析，以及血管血流的测量 (流动介导的扩张)和灌流(近红外光谱)，以充分描述亚硝酸盐的内皮效应。 目标3是探索性的，重点是亚硝酸盐疗法对身体机能、日常活动和疲劳性的影响。 身体机能是根据生理指标(即最大血氧更新(VO2)和 次最大工作负荷下的VO2)和临床措施(即耐力[对70%次最大工作负荷的耐受性 最大VO2直到筋疲力尽]、6分钟步行距离、短物理性能电池和手柄 力量)。每天的活动量是用加速度计测量的。可成熟性是根据感知的和 绩效指标。总体而言，这项提议提供了一个关键的、面向机械的观点，涉及 亚硝酸盐的功效；如果线粒体生物能量学在这一分析中得到改进，未来的研究可以探索 亚硝酸盐作为一种帮助克服老年久坐不动的治疗方法的效用。

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.