The Role of Mitochondrial and Redox Alterations in the Skeletal Myopathy Associated with Chronic Kidney Disease

Abstract

Significance: An estimated 700 million people globally suffer from chronic kidney disease (CKD). In addition to increasing cardiovascular disease risk, CKD is a catabolic disease that results in a loss of muscle mass and function, which are strongly associated with mortality and a reduced quality of life. Despite the importance of muscle health and function, there are no treatments available to prevent or attenuate the myopathy associated with CKD. Recent Advances: Recent studies have begun to unravel the changes in mitochondrial and redox homeostasis within skeletal muscle during CKD. Impairments in mitochondrial metabolism, characterized by reduced oxidative phosphorylation, are found in both rodents and patients with CKD. Associated with aberrant mitochondrial function, clinical and preclinical findings have documented signs of oxidative stress, although the molecular source and species are ill-defined. Critical Issues: First, we review the pathobiology of CKD and its associated myopathy, and we review muscle cell bioenergetics and redox biology. Second, we discuss evidence from clinical and preclinical studies that have implicated the involvement of mitochondrial and redox alterations in CKD-associated myopathy and review the underlying mechanisms reported. Third, we discuss gaps in knowledge related to mitochondrial and redox alterations on muscle health and function in CKD. Future Directions: Despite what has been learned, effective treatments to improve muscle health in CKD remain elusive. Further studies are needed to uncover the complex mitochondrial and redox alterations, including post-transcriptional protein alterations, in patients with CKD and how these changes interact with known or unknown catabolic pathways contributing to poor muscle health and function. Antioxid. Redox Signal. 38, 318-337.

Keywords: cachexia; metabolism; renal; skeletal muscle; uremia.

FIG. 1.

Mechanisms involved in the myopathic phenotype of the CKD patient. CKD patients commonly suffering from a debilitating myopathic phenotype consisting of muscle weakness, fatigue, and exercise intolerance. Impaired renal function drives pathological adaptations systemically and locally in skeletal muscle that contribute to the development and progression of this myopathy. Collectively, these pathological alterations contribute to low physical activity levels and a sedentary lifestyle, which further exacerbate the myopathy symptoms. CKD, chronic kidney disease. Illustration created using BioRender.com

FIG. 2.

An overview of mitochondrial energy transduction. In skeletal muscle, the mitochondrion plays a crucial role in converting the fuel consumed (glucose, fats, proteins) into a useable energy source (ATP) that is necessary to sustain the activities of the myofiber. Through a series of biochemical redox reactions, electrons are transferred from carbon fuels into the ETS via electron carriers (NAD⁺ and FAD⁺). The movement of electrons through the ETS powers the translocation of protons from the matrix to the IMS, creating the proton motive force that subsequently drives ATP synthesis. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT, carnitine palmitoyltransferase; Cyt C, cytochrome c; ETS, electron transport system; FAD, flavin adenine dinucleotide; FFAs, free fatty acids; H⁺, proton; IMM, inner mitochondrial membrane; IMS, intermembrane space; LDH, lactate dehydrogenase; NAD, nicotinamide adenine dinucleotide; OMM, outer mitochondrial membrane; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid. Illustration created using BioRender.com

FIG. 3.

An overview of redox homeostasis in skeletal muscle. (A) The major sources of reducing power (NADPH) in the cytosol and mitochondria that support antioxidant enzymes. (B) Major sources of ROS production and scavenging pathways in the cytosol and mitochondrion. AKG, alpha ketoglutarate; CAT, catalase; CYPs, cytochrome P450 enzymes; DHODH, dihydroorotate dehydrogenase; GPX, glutathione peroxidase; GR, glutathione reductase; GRX, glutaredoxin; GSH, reduced glutathione; GSSG, oxidized glutathione; H₂O₂, hydrogen peroxide; IDH, isocitrate dehydrogenase; Mal, malate; MAO, monoamine oxidase; ME, malic enzyme; NADP, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOX, NADPH oxidase; ONOO⁻, peroxynitrite; PRX, peroxiredoxin; ROS, reactive oxygen species; SOD, superoxide dismutase; TR, thioredoxin reductase; TRX, thioredoxin; XO, xanthine oxidase. Illustration created using BioRender.com

FIG. 4.

Altered mitochondrial metabolism and redox homeostasis in CKD. Muscle from patients or animals with CKD display histological signs of mitochondrial pathology (cristae swelling, fragmentation, mitophagosome accumulation), reduced mitochondrial mass, enzyme activity, and oxygen consumption. Uremic toxin accumulation is associated with impaired mitochondrial metabolism through reductions in dehydrogenase enzyme activity. Biomarkers of oxidative stress are commonly reported in CKD muscle; however, the sources are not fully understood. NADPH (NOX) enzymes display increased abundance and activity in CKD muscle, whereas a few studies have thoroughly evaluated the mitochondria as a source contributing to muscle oxidative stress in CKD. The biochemical alterations in mitochondrial metabolism and redox homeostasis are consistent with the observed myopathic phenotype, including muscle atrophy, weakness, and increased fatiguability—all features that have been directly linked to muscle pathologies in non-CKD conditions. Illustration created using BioRender.com

FIG. 5.

A review of redox signaling and muscle atrophy. There is an abundance of literature documenting that key catabolic and anabolic pathways in skeletal muscle are altered through redox mechanisms. Increase in ROS contributes to a variety of catabolic pathways, including activation of calpains, caspase 3, autophagy, E3-ubiquitin ligases, NF-kappa B (NF-κB), and atrogene expression (FOXOs). Moreover, elevated ROS levels impair protein synthesis via the IGF1-mTORC1 pathway. Overall, these conditions precipitate an imbalance of protein synthesis and degradation rates, resulting in loss of muscle proteins and atrophy. Illustration created using BioRender.com

FIG. 6.

Mitochondrial and redox control of muscle stem function. Emerging evidence has shed light on the importance of metabolic and redox changes in the biology of resident muscle stem cells. Quiescent satellite cells rely heavily on fatty acid oxidation and drive suppression of myogenic gene transcription via histone deacetylation. In contrast, activated/proliferating satellite cells activate glycolysis and decrease mitochondrial OXPHOS leading to histone acetylation and expression of key myogenic transcription factors. Finally, a robust increase in mitochondrial mass and OXPHOS are required for differentiation and maturation. Coincidently, ROS levels increase through the course of differentiation/maturation. The impact of CKD on muscle stem energetics and redox homeostasis represents an unexplored area of research. OXPHOS, oxidative phosphorylation. Illustration created using BioRender.com