The molecular mechanism of skeletal muscle autophagy in uremia: a study based on the FOXO3a/Nrf2 signaling pathway

Ma Juan; Guo Yinxue; Hu Maorong

doi:10.13406/j.cnki.cyxb.003556

您当前的位置：

首页 >

文章列表页 >

The molecular mechanism of skeletal muscle autophagy in uremia: a study based on the FOXO3a/Nrf2 signaling pathway

Basic research | 更新时间：2025-10-21

- The molecular mechanism of skeletal muscle autophagy in uremia: a study based on the FOXO3a/Nrf2 signaling pathway
- Journal of Chongqing Medical University Vol. 49, Issue 8, Pages: 986-993(2024)
- 作者机构：
  
  贵州中医药大学第一附属医院肾内科，贵阳 550002
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003556
  CLC： R730.6
- Received：04 July 2023，
  
  Revised：2023-12-11，
  
  Accepted：15 December 2023，
  
  Published：28 August 2024
- 稿件说明：
移动端阅览
马娟,郭银雪,胡茂蓉.基于FOXO3a/Nrf2信号通路探讨尿毒症骨骼肌自噬的分子机制[J].重庆医科大学学报,2024,49(8):986-993.

Ma Juan,Guo Yinxue,Hu Maorong.The molecular mechanism of skeletal muscle autophagy in uremia: a study based on the FOXO3a/Nrf2 signaling pathway[J].Journal of Chongqing Medical University,2024,49(8):986-993.
马娟,郭银雪,胡茂蓉.基于FOXO3a/Nrf2信号通路探讨尿毒症骨骼肌自噬的分子机制[J].重庆医科大学学报,2024,49(8):986-993. DOI： 10.13406/j.cnki.cyxb.003556.

Ma Juan,Guo Yinxue,Hu Maorong.The molecular mechanism of skeletal muscle autophagy in uremia: a study based on the FOXO3a/Nrf2 signaling pathway[J].Journal of Chongqing Medical University,2024,49(8):986-993. DOI： 10.13406/j.cnki.cyxb.003556.

摘要

目的

探讨叉头盒（forkhead box，FOX）O蛋白3a（forkhead box O3a，FOXO3a）/转录因子NF-E2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf2）信号通路的调节尿毒症骨骼肌自噬的机制。

方法

24只小鼠随机分为假手术组（Sham组）、慢性肾病（chronic kidney disease，CKD）组和CKD+AST-120（AST）组，每组8只。通过5/6肾切除术建立CKD模型。在肾切除术后4周，CKD+AST组小鼠给予含AST-120粉末（尿毒毒素的木炭吸附剂）饮食，持续8周。透射电子显微镜观察腓肠肌组织中的自噬溶酶体。C2C12小鼠成肌细胞分为对照（Control，Con）组、硫酸吲哚酚（indophenol sulfate，IS）组、IS+si-FOXO3a组。实时RT-PCR和蛋白质印迹法分析FOXO3a表达情况。Giemsa染色对C2C12肌管直径进行量化。

结果

与CKD组相比，CKD+AST组血清IS水平和腓肠肌组织中FOXO3a表达、自噬溶酶体的数量明显降低（

0.05），以及腓肠肌、胫骨前肌、比目鱼肌质量明显增加（

0.05）。与IS组相比，IS+si-FOXO3a组C2C12细胞中FOXO3a、肌肉萎缩盒基因（Muscle Atrophy F-box，atrogin-1）肌肉环脂蛋白1（muscle RING-finger protein-1，MuRF-1）的表达和细胞自噬通量明显降低（

0.05），以及细胞直径明显增加（

0.05）。与Sham组相比，CKD组小鼠腓肠肌组织中Kelch样ECH相关蛋白1（Kelch-like ECH-associated protein 1，KEAP1）表达明显升高（

0.05），和NRF2表达明显降低（

0.05）。AST治疗逆转了CKD小鼠腓肠肌组织中这些蛋白的变化。si-NRF2逆转了FOXO3a敲低对自噬流量的抑制作用。

结论

IS可能通过持续刺激FOXO3a-KEAP1-NRF2轴促进骨骼肌过度自噬，参与尿毒症少肌症的发病机制。

Abstract

Objective

To explore the role of the forkhead box O3a（FOXO3a）/nuclear factor erythroid 2-related factor 2（Nrf2） signaling pathway in regulating skeletal muscle autophagy in uremia.

Methods

Twenty-four mice were randomly divided into sham group，chronic kidney disease（CKD） group，and CKD+AST-120（AST） group，with eight mice in each group. A CKD model was established by using the 5/6 nephrectomy method. Four weeks after nephrectomy，the mice in the CKD+AST group were fed with powder chow containing AST-120（a charcoal adsorbent for uremic toxin） for eight weeks. Autolysosomes in the gastrocnemius muscle were observed using a transmission electron microscope. C2C12 myoblasts were divided into control group，indophenol sulfate group（IS），and IS+si-FOXO3a group. The expression of FOXO3a was determined using real-time RT-PCR and Western blot. The diameter of C2C12 myotubes was measured with Giemsa staining.

Results

Compared with the CKD group，the CKD+AST group showed significant decreases in serum IS level and FOXO3a expression and the number of autolysosomes in the gastrocnemius tissue and significant increases in the masses of the gastrocnemius muscle，anterior tibial muscle，and soleus muscle（all

0.05）. Compared with the IS group，the IS+si-FOXO3a group showed significant reductions in the expression of FOXO3a，atrogin-1，and muscle RING-finger protein-1 in C2C12 cells as well as the autophagic flux of the cells and a significantly increased cell diameter（all

0.05）. Compared with the sham group，the CKD group showed significantly increased expression of Kelch-like ECH-associated protein 1（KEAP1） and significantly decreased Nrf2 expression in the gastrocnemius tissue（both

0.05）. AST treatment reversed the changes in these proteins in the gastrocnemius tissue of CKD mice. Si-Nrf2 reversed the inhibitory effect of FOXO3a knockdown on autophagic flux.

Conclusion

IS may promote skeletal muscle autophagy by continuously stimulating the FOXO3A-KEAP1-Nrf2 axis to participate in the pathogenesis of uremic sarcopenia.

关键词

Keywords

references

王蕤婷，黄新忠 . 慢性肾脏病肌萎缩的发病机制及诊疗进展 [J ] . 上海医学， 2022 ， 45 （ 12 ）： 862 - 867 .

Wang RT ， Huang XZ . Progress in pathogenesis，diagnosis and treatment of muscular atrophy in chronic kidney disease [J ] . Shanghai Med J ， 2022 ， 45 （ 12 ）： 862 - 867 .

马迎春 . 慢性肾脏病患者运动康复的管理 [J ] . 肾脏病与透析肾移植杂志， 2022 ， 31 （ 4 ）： 353 - 354 .

Ma YC . Management of implement exercise rehabilitation training in patients with chronic kidney disease [J ] . Chin J Nephrol Dial Transplant ， 2022 ， 31 （ 4 ）： 353 - 354 .

Lee SM ， Han MY ， Kim SH ， et al . Indoxyl Sulfate Might Play a Role in Sarcopenia，While Myostatin Is an Indicator of Muscle Mass in Patients with Chronic Kidney Disease：analysis from the RECOVERY Study [J ] . Toxins ， 2022 ， 14 （ 10 ）： 660 .

Hou YC ， Liu YM ， Liao MT ， et al . Indoxyl sulfate mediates low handgrip strength and is predictive of high hospitalization rates in patients with end-stage renal disease [J ] . Front Med ， 2023 ， 10 ： 1023383 .

Caldiroli L ， Armelloni S ， Eskander A ， et al . Association between the uremic toxins indoxyl-sulfate and p-cresyl-sulfate with sarcopenia and malnutrition in elderly patients with advanced chronic kidney disease [J ] . Exp Gerontol ， 2021 ， 147 ： 111266 .

Troutman AD ， Arroyo E ， Lim K ， et al . Skeletal muscle complications in chronic kidney disease [J ] . Curr Osteoporos Rep ， 2022 ， 20 （ 6 ）： 410 - 421 .

Kang SH ， Lee HA ， Kim M ， et al . Forkhead box O 3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing’s syndrome [J ] . Am J Physiol Endocrinol Metab ， 2017 ， 312 （ 6 ）： 495 - 507 .

Alcalde-Estévez E ， Sosa P ， Asenjo-Bueno A ， et al . Uraemic toxins impair skeletal muscle regeneration by inhibiting myoblast proliferation，reducing myogenic differentiation，and promoting muscular fibrosis [J ] . Sci Rep ， 2021 ， 11 （ 1 ）： 512 .

Radloff J ， Latic N ， Pfeiffenberger U ， et al . A phosphate and calcium-enriched diet promotes progression of 5/6-nephrectomy-induced chronic kidney disease in C57BL/6 mice [J ] . Sci Rep ， 2021 ， 11 （ 1 ）： 14868 .

Li LC ， Chen WY ， Chen JB ， et al . The AST-120 recovers uremic toxin-induced cognitive deficit via NLRP3 inflammasome pathway in astrocytes and microglia [J ] . Biomedicines ， 2021 ， 9 （ 9 ）： 1252 .

Fujita K ， Nonaka T ， Kutsuno R ， et al . Electrochemical sensing of the secretion of indoxyl sulfate in a rat intestinal loop using a self-assembled monolayer-modified gold bead electrode [J ] . Talanta ， 2022 ， 247 ： 123551 .

Lu CH ， Yu R ， Zhang C ， et al . Protective autophagy decreases lorlatinib cytotoxicity through Foxo3a-dependent inhibition of apoptosis in NSCLC [J ] . Cell Death Discov ， 2022 ， 8 （ 1 ）： 221 .

Ali T ， Rahman SU ， Hao Q ， et al . Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation [J ] . J Pineal Res ， 2020 ， 69 （ 2 ）： e12667 .

Jin H ， Zhang L ， He J ， et al . Role of FOXO3a transcription factor in the regulation of liver oxidative injury [J ] . Antioxidants ， 2022 ， 11 （ 12 ）： 2478 .

Xia QH ， Huang XB ， Huang JR ， et al . The role of autophagy in skeletal muscle diseases [J ] . Front Physiol ， 2021 ， 12 ： 638983 .

Takkavatakarn K ， Phannajit J ， Udomkarnjananun S ， et al . Association between indoxyl sulfate and dialysis initiation and cardiac outcomes in chronic kidney disease patients [J ] . Int J Nephrol Renovasc Dis ， 2022 ， 15 ： 115 - 126 .

Hamza E ， Vallejo-Mudarra M ， Ouled-Haddou H ， et al . Indoxyl sulfate impairs erythropoiesis at BFU-E stage in chronic kidney disease [J ] . Cell Signal ， 2023 ， 104 ： 110583 .

Lai S ， Muscaritoli M ， Andreozzi P ， et al . Sarcopenia and cardiovascular risk indices in patients with chronic kidney disease on conservative and replacement therapy [J ] . Nutrition ， 2019 ， 62 ： 108 - 114 .

Milan G ， Romanello V ， Pescatore F ， et al . Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy [J ] . Nat Commun ， 2015 ， 6 ： 6670 .

Jang DE ， Song JB ， Park JW ， et al . Protein kinase CK2 activates Nrf2 via autophagic degradation of Keap1 and activation of AMPK in human cancer cells [J ] . BMB Rep ， 2020 ， 53 （ 5 ）： 272 - 277 .

Lu Q ， Zhang Y ， Zhao C ， et al . Copper induces oxidative stress and apoptosis of hippocampal neuron via pCREB/BDNF/and Nrf2/HO-1/NQO1 pathway [J ] . J Appl Toxicol ， 2022 ， 42 （ 4 ）： 694 - 705 .

Shekh-Ahmad T ， Eckel R ， Dayalan Naidu S ， et al . KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy [J ] . Brain ， 2018 ， 141 （ 5 ）： 1390 - 1403 .

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

TMEM9 promotes the proliferation and invasion of prostate cancer by affecting autophagy

Role of Sp1/ABCA1 signaling pathway in uremic atherosclerosis and its regulatory mechanism

Physical exercise ameliorates cognitive impairment caused by sleep deprivation by modulating autophagy

Picroside Ⅱ improves Aβ-induced learning and memory deficits in mice by enhancing autophagy

Bakuchiol initiates autophagy to reduce β-phosphoglycerol-induced calcification of mouse vascular smooth muscle cells

Related Author

Su Shuai

Zhang Jindong

Luo Yu

Song Liangdong

Liu Hengchuan

Zhu Huixuan

Wang Delin

Huang Ningchuan

Related Institution

Department of Urology，The First Affiliated Hospital of Chongqing Medical University

Department of Neurology，University-Town Hospital of Chongqing Medical University

Chongqing Institute of Medicinal Plant Cultivation， Chongqing College of Traditional Chinese Medicine

Pediatric Research Institute，National Clinical Research Center for Child Health and Disorders， Ministry of Education Key Laboratory of Child Development and Disorders，Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders， Children’s Hospital of Chongqing Medical University

Vascular Surgery Department，The Affiliated Hospital of Southwest Medical University；Institute of Cardiovascular Research，Key Laboratory of Medical Electrophysiology of Ministry of Education，Medical Electrophysiological Ley Laboratory of Sichuan Province

⁰