Molecular Medicine Branch, NIDDK, NIH, Bethesda, MD, United States; Penn State Health Milton S. Hershey Medical Center, Department of Anesthesiology, Hershey, PA, United States.
Molecular Medicine Branch, NIDDK, NIH, Bethesda, MD, United States; Icahn School of Medicine, Mt. Sinai, New York, NY, United States.
Nitric Oxide. 2018 May 1;75:1-7. doi: 10.1016/j.niox.2018.01.010. Epub 2018 Jan 31.
Rodent skeletal muscle has high levels of nitrate ions and this endogenous nitrate reservoir can supply nitrite/nitric oxide (NO) for functional hyperemia and/or for other physiological processes in muscle during exercise. Mice with a NOS1 knockout have markedly reduced muscle nitrate levels, suggesting NO production by NOS and its reaction with oxymyoglobin as a source of nitrate. However, oxygen levels are normally low in most internal organs, which raises the possibility that nitrate-derived NO pathway is physiologically important even at "normoxia", and muscle nitrate reservoir is the main endogenous NO backup when exogeneous (dietary) nitrate intake is low. Using dietary nitrate manipulations, we explore the importance of diet for maintaining and renewal of muscle nitrate reservoir and its levels in other tissues. We found that skeletal muscle nitrate is extensively used when nitrate in diet is low. One week of nitrate starvation leads to dramatic nitrate depletion in skeletal muscle and a substantial decrease in liver. Nitrate depleted from skeletal muscle during starvation is quickly recovered from new dietary sources, with an unexpected significant "overload" compared with animals not subjected to nitrate starvation. Our results suggest the importance of dietary nitrate for nitrate reserves in muscle and in other tissues, when compared with endogenous NOS-derived sources. This requires an active transport mechanism for sequestering nitrate into cells, stimulated by lack of dietary nitrate or other enzymatic changes. These results confirm the hypothesis that muscle is a major storage site for nitrate in mammals.
啮齿动物的骨骼肌中含有高水平的硝酸盐离子，这种内源性硝酸盐储备可以为运动时的功能性充血和/或肌肉中的其他生理过程提供亚硝酸盐/一氧化氮 (NO)。NOS1 基因敲除的小鼠骨骼肌中的硝酸盐水平明显降低，这表明 NOS 产生的 NO 及其与氧合肌红蛋白的反应是硝酸盐的来源。然而，大多数内脏器官中的氧气水平通常较低，这增加了这样一种可能性，即在“常氧”条件下，硝酸盐衍生的 NO 途径即使在正常情况下也是生理上重要的，并且当外源性（饮食）硝酸盐摄入量低时，肌肉硝酸盐储备是主要的内源性 NO 备用来源。通过饮食硝酸盐处理，我们探讨了饮食对于维持和更新肌肉硝酸盐储备及其在其他组织中的水平的重要性。我们发现，当饮食中的硝酸盐含量较低时，骨骼肌会大量使用硝酸盐。一周的硝酸盐饥饿会导致骨骼肌中的硝酸盐大量消耗，并导致肝脏中的硝酸盐含量显著下降。在饥饿期间从骨骼肌中消耗的硝酸盐会从新的饮食来源中迅速恢复，但与未经历硝酸盐饥饿的动物相比，会出现出乎意料的显著“过载”。我们的研究结果表明，与内源性 NOS 衍生的来源相比，饮食硝酸盐对于肌肉和其他组织中的硝酸盐储备非常重要。这需要一种主动运输机制将硝酸盐隔离到细胞中，这种机制受到饮食中缺乏硝酸盐或其他酶变化的刺激。这些结果证实了这样一种假设，即肌肉是哺乳动物中硝酸盐的主要储存部位。
