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

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.

Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease

“…Previous studies have reported that mice and human with CKD displayed lower mitochondrial content/density in skeletal muscle (14,20,47,58), which contrast the observations herein. There are several biomarkers used to estimate mitochondrial content in muscle, however they vary widely in accuracy when compared to electron microscopy (a gold standard) (59).…”

Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia

“…Several experiments indicate mitochondrial dysfunction in the skeletal muscle of patients with CKD ( Gamboa et al, 2016 ; Sato et al, 2016 ; Kikuchi et al, 2019 ; Thome et al, 2019 ; Xu et al, 2020 ). Both mitochondrial volume density and mtDNA copy numbers were decreased in skeletal biopsy specimens sampled from kidney failure patients who underwent HD ( Gamboa et al, 2016 ) or PD ( Xu et al, 2020 ) ( Figures 1B , 2 ). A recent human study assessed the phosphocreatine recovery time constant to measure mitochondrial function in the knee extensors using with 31 P magnetic resonance spectroscopy ( Gamboa et al, 2020 ).…”

“…Several studies have recognized the impaired role of the PDHC at a molecular level in the mitochondria of skeletal muscle in CKD sarcopenia ( Sato et al, 2016 ; Thome et al, 2019 ; Xu et al, 2020 ). The PDHC is essential to energy production under anaerobic condition, as the enzyme converts pyruvate to acetyl-CoA for the TCA cycle.…”

“…In murine C2C12 myocytes, cell cultures exposed to a uremic toxin promote glycolysis with excess antioxidative responses, leading to mitochondrial TCA cycle down-regulation and ATP shortage ( Sato et al, 2016 ). Moreover, PDHC activity and phospho-PDH (S293) are decreased in the skeletal muscle of patients with advanced CKD, whereas PDK4 protein levels are upregulated ( Xu et al, 2020 ). Treatment of CKD in mice with dichloroacetate to activate PDHC improved the treadmill running test distance ( Tamaki et al, 2014 ).…”

Response of the oxygen uptake efficiency slope to exercise training in patients with chronic kidney disease

“…Skeletal muscle mitochondrial abnormalities have been noted in patients with CKD [28]. To date, data from human studies are lacking, but skeletal muscle biopsies taken from CKD patients have revealed reduced mitochondrial density and mitochondrial DNA copy numbers, abnormal morphology, and reduced activity of pyruvate dehydrogenase [29], a key coupling enzyme in cellular respiration [30]. Dysfunctional mitochondria are an important source of reactive oxygen species, implicated in cardiovascular morbidity and mortality [31,32].…”