Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease

• Published in: Nephrology (Carlton, Vic.) Vol. 25; no. 3; pp. 230 - 238
• Main Authors: Xu, Chenqi, Kasimumali, Ayijiaken, Guo, Xiangjiang, Lu, Renhua, Xie, Kewei, Zhu, Mingli, Qian, Yingying, Chen, Xiaohuan, Pang, Huihua, Wang, Qin, Fan, Zhuping, Dai, Huili, Mou, Shan, Ni, Zhaohui, Gu, Leyi
• Format: Journal Article
• Language: English
• Published: Melbourne John Wiley & Sons Australia, Ltd 01.03.2020; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Dehydrogenases; DRP1; Enzymatic activity; Female; Gene expression; Hand Strength; handgrip strength; Hemoglobin; Humans; Kidney diseases; Kinases; Male; MFN‐1; Middle Aged; Mitochondria; Mitochondria, Muscle - physiology; Morphology; Muscle Weakness - etiology; Muscle, Skeletal - enzymology; Musculoskeletal system; Patients; PGC‐1Α; Protein Kinases - physiology; pyruvate dehydrogenase; Pyruvic acid; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - physiopathology; Skeletal muscle; Transmission electron microscopy; Up-Regulation; Western blotting; pyruvate dehydrogenase; PGC-1Α; handgrip strength; MFN-1; DRP1
• ISSN: 1320-5358; 1440-1797
• DOI: 10.1111/nep.13606

ABSTRACT Aim Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post‐translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle. Methods Twenty patients with stage 4–5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other eight non‐CKD surgical subjects’ muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real‐time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology. Results CKD patients had lower HGS than non‐CKD subjects, and HGS was correlated with gender, age, haemoglobin and albumin. Mitochondria were decreased in end‐stage renal disease (ESRD) patients muscle. Mfn‐1 expression and phospho‐Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phospho‐PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated. Conclusion Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients. SUMMARY AT A GLANCE The present study investigated changes in mitochondrial morphology and pyruvate dehydrogenase (PDH) activity and pyruvate dehydrogenase kinase 4 (PDK4) expression in muscle of human chronic kidney disease (CKD). Decreased mitochondria in association with reduced Mfn‐1 and phospho‐Drp1(S637)/Drp1 ratio suggested dysfunctional mitochondrial dynamics, which, together with reduced PDH activity and PDK4 upregulation, may account for muscle weakness in CKD.