Yue Yue Zhang1, Li Jie Gu1, Jin Fang Bao2, Wei Jie Yuan3, Juan Huang1, Min Chao Cai1, Hong Lei Yu1, Wei Zhang1. 1. Devision of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China. 2. Devision of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China. bamboobao@163.com. 3. Devision of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China. ywj4169@163.com.
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.
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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