Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida.
Division of Vascular Surgery and Endovascular Therapy, University of Florida, Gainesville, Florida.
Am J Physiol Renal Physiol. 2022 Nov 1;323(5):F577-F589. doi: 10.1152/ajprenal.00156.2022. Epub 2022 Aug 25.
End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, confirming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis. Creation of an arteriovenous fistula (AVF) is the preferred approach for dialysis access, but some patients experience hand dysfunction after AVF creation. In this study, we provide a detailed metabolomic analysis of the limb muscle in a murine model of AVF. AVF creation resulted in metabolite changes associated with an energetic crisis and myosteatosis that associated with limb function.
终末期肾病是慢性肾脏病（CKD）的最晚期，需要肾脏替代治疗或肾移植来维持生命。为了实现持久的透析通路，动静脉瘘（AVF）的建立已成为首选方法。不幸的是，相当一部分接受 AVF 的患者会出现某种形式的手部功能障碍；然而，这些副作用的机制尚不清楚。在这项研究中，我们使用磁共振波谱分析研究了 CKD 小鼠接受髂动脉 AVF 放置后的肌肉代谢组。为了诱导 CKD，C57BL6J 小鼠喂食添加腺嘌呤的饮食 3 周，然后随机接受 AVF 或假手术。手术后 2 周，迅速解剖股四头肌并冷冻用于代谢物提取和随后的磁共振分析。主成分分析表明组间有明显分离，证实了接受 AVF 的小鼠具有独特的代谢组。AVF 的创建导致肌酸、ATP 和 AMP 水平降低，IMP 和几种三羧酸循环代谢物水平升高，表明存在严重的能量应激。Pearson 相关和多元线性回归分析确定了几种与肢体功能（握力、步态速度和线粒体呼吸）测量密切相关的代谢物。总之，AVF 的创建在远侧骨骼肌中产生了独特的代谢组谱，表明存在能量危机和肌脂肪变性。AVF 的创建是透析通路的首选方法，但一些患者在 AVF 创建后会出现手部功能障碍。在这项研究中，我们提供了 AVF 模型中小鼠肢体肌肉的详细代谢组学分析。AVF 的创建导致与能量危机和肌脂肪变性相关的代谢物变化，与肢体功能相关。
