Abstract
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.
Results
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.
Conclusions
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.
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Acknowledgements
We are indebted to the patients, whose participation made this study possible. We thank Zhang Boyan at the Department of Central Laboratory, Eye and ENT Hospital of Fudan University, for technical support for confocal imaging and Chen Xinyu at the Shanghai Jiaotong University School of Medicine for technical support for electron microscopy. We thank the collaborators, who assisted in obtaining the tissue studied in the research, as follows: Xu Mindong at the Department of Nephrology, Tongji University Affiliated Shanghai Yangpu District Central Hospital; Han Guofeng and Hu Weifeng at the Department of Nephrology, No. 455 Hospital of People’s Liberation Army, China; Xi Xiaowei and Chen Yongping at the Department of Obstetrics and Gynecology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital; Peng Zhihai at the Department of General Surgery, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital. We thank Pubsci Limited for editorial assistance.
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Zhang, Y.y., Gu, L.j., Huang, J. et al. CKD autophagy activation and skeletal muscle atrophy—a preliminary study of mitophagy and inflammation. Eur J Clin Nutr 73, 950–960 (2019). https://doi.org/10.1038/s41430-018-0381-x
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DOI: https://doi.org/10.1038/s41430-018-0381-x
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