系统性炎症与维持性血液透析患者骨骼肌蛋白过度分解代谢有关。
Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients.
机构信息
Division of Nephrology, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, USA.
CSRD&D, Veterans Administration Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
出版信息
JCI Insight. 2017 Nov 16;2(22). doi: 10.1172/jci.insight.95185.
BACKGROUND
Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients.
METHODS
Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models.
RESULTS
Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease.
CONCLUSION
These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation.
FUNDING
This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.
背景
系统性炎症和肌肉减少症在维持性血液透析（MHD）患者中普遍存在且并存。我们旨在确定系统性炎症对 MHD 患者骨骼肌蛋白代谢的影响。
方法
通过稳定同位素动力学研究评估全身和骨骼肌蛋白周转率。我们将整合素 β1 基因敲除 CKD 小鼠模型骨骼肌组织中的 E1、E214K、E3αI、E3αII、MuRF-1 和 atrogin-1 的表达纳入其中。
结果
在 129 名平均（±标准差）年龄为 47±12 岁的患者中，74%为非裔美国人，73%为男性，22%患有糖尿病。中位高敏 C 反应蛋白（hs-CRP）浓度为 13（四分位距 0.8，33）mg/L。hs-CRP 与前臂骨骼肌蛋白合成、降解和净前臂骨骼肌蛋白平衡之间存在统计学显著关联（所有 P<0.001）。在调整临床和人口统计学混杂因素以及在排除患有糖尿病的患者的敏感性分析后，这些关联仍然具有统计学意义。在试图确定这种相关性涉及的潜在机制时，我们发现慢性肾脏病动物模型的骨骼肌组织中 E1、E214K、E3αI、E3αII、MuRF-1 和 atrogin-1 的表达增加。
结论
这些数据表明，系统性炎症是 MHD 患者骨骼肌蛋白动态平衡的一个强烈和独立的决定因素，为使用针对潜在系统性炎症的细胞因子治疗患者的进一步研究提供了依据。
资助
本研究部分得到 NIH 授予的 R01 DK45604 和 1K24 DK62849 研究基金、国家转化医学科学中心授予的临床转化科学奖 UL1-TR000445、退伍军人事务部 merit 奖 I01 CX000414、SatelliteHealth Normon Coplon 外展赠款计划以及 FDA 授予的 000943 号赠款的支持。
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