Association of chronic kidney disease with mitochondrial dysfunction in the skeletal muscle

Abstract

Advanced chronic kidney disease (CKD) is associated with impaired exercise capacity, skeletal muscle dysfunction, and oxidative stress. Mitochondria are the primary source of production of energy and generation of reactive oxygen species (ROS). We hypothesized that skeletal muscle dysfunction and oxidative stress in CKD are, in part, due to impaired energy production and heightened ROS generation by mitochondria. Mitochondrial state 3 respiration (measured as the maximal rate of ADP conversion to ATP, using pyruvate and malate as substrates) and mitochondrial complex I enzyme activity were determined in the gastrocnemius muscle of male SD rats 14 weeks after 5/6 nephrectomy (CKD) or sham‐operation (control). The CKD group exhibited proteinuria, hypertension, azotemia, and reduced weight gain. This was associated with significant reduction (−39%) of state 3 mitochondrial respiration and a significant increase in the mitochondrial complex I enzyme activity. The latter is the first step in oxidative phosphorylation by catalyzing oxidation of reduced nicotinamide adenine dinucleotide (NADH→NAD+), a process which is linked to production of ROS. In conclusion, CKD results in impaired mitochondrial respiration, depressed energy production and increased ROS generation in the skeletal muscle. These events can simultaneously contribute to the reduction of exercise capacity and oxidative stress in CKD.