Devision of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China.
Eur J Clin Nutr. 2019 Jun;73(6):950-960. doi: 10.1038/s41430-018-0381-x. Epub 2019 Jan 3.
BACKGROUND/OBJECTIVES: Long-lived proteins and organelles, such as mitochondria and the sarcoplasmic reticulum, are degraded by autophagy. However, the specific role of autophagy in chronic kidney disease (CKD) muscle atrophy is still undefined.
SUBJECTS/METHODS: This was a cross-sectional study with 20 subjects and 11 controls. Autophagy induction was studied in human skeletal muscle biopsies from CKD patients and controls by comparing the cross-sectional areas of muscle fibers, protein, and mRNA expression of autophagy-related genes and the appearance of autophagosomes.
The cross-sectional area of muscle fibers was decreased in CKD patients as compared with the control group. CKD was associated with activated autophagy and mitophagy, as measured by the elevated mRNA and protein expression of BNIP3, (microtubule-associated proteins 1 A/1B light chain 3, also MAP1LC3) LC3, p62, PINK1, and PARKIN in the skeletal muscle and isolated mitochondria of the CKD group. Electron microscopy and immunohistofluorescence analysis showed mitochondrial engulfment by autophagosomes. Mitophagy was further demonstrated by the colocalization of LC3 and p62 puncta with the mitochondrial outer membrane protein TOM20. In addition, degradative FOXO3 (Forkhead box O3) was activated and synthetic mTOR (mammalian target of rapamycin) was inhibited, whereas the upstream mediators VPS34 (class III PI3-kinase) and AKT (protein kinase B, PKB) were activated in CKD patients.
Hyperactive autophagy and mitophagy may play important roles in CKD muscle atrophy. Autophagy was activated by FOXO3 translational factors in the skeletal muscle tissues of CKD patients, which maybe a new way of intervention for CKD muscle atrophy.
背景/目的：长寿蛋白和细胞器，如线粒体和肌浆网，可被自噬所降解。然而，自噬在慢性肾脏病（CKD）肌肉萎缩中的具体作用仍未明确。
研究对象/方法：本研究为一项横断面研究，共纳入 20 名 CKD 患者和 11 名对照者。通过比较 CKD 患者和对照者骨骼肌活检的肌纤维横截面积、自噬相关基因的蛋白和 mRNA 表达以及自噬体的出现，研究自噬的诱导作用。
与对照组相比，CKD 患者的肌纤维横截面积减小。CKD 患者存在自噬和线粒体自噬的激活，表现在骨骼肌和分离的 CKD 组线粒体中 BNIP3、（微管相关蛋白 1A/1B 轻链 3，也称为 MAP1LC3）LC3、p62、PINK1 和 PARKIN 的 mRNA 和蛋白表达升高。电子显微镜和免疫荧光分析显示了自噬体对线粒体的吞噬作用。通过 LC3 和 p62 斑点与线粒体外膜蛋白 TOM20 的共定位进一步证明了线粒体自噬。此外，在 CKD 患者中，降解性 FOXO3（叉头框 O3）被激活，合成性 mTOR（哺乳动物雷帕霉素靶蛋白）被抑制，而上游介质 VPS34（III 型 PI3-激酶）和 AKT（蛋白激酶 B，PKB）被激活。
过度活跃的自噬和线粒体自噬可能在 CKD 肌肉萎缩中发挥重要作用。自噬在 CKD 患者的骨骼肌组织中被 FOXO3 翻译因子激活，这可能是治疗 CKD 肌肉萎缩的新方法。
