Skeletal Muscle Phenotype in Patients Undergoing Long-Term Hemodialysis Awaiting Kidney Transplantation

Abstract

Background and objectivesAge and comorbidity-related sarcopenia represent a main cause of muscle dysfunction in patients on long-term hemodialysis. However, recent findings suggest muscle abnormalities that are not associated with sarcopenia. The aim of this study was to isolate functional and cellular muscle abnormalities independently of other major confounding factors, including malnutrition, age, comorbidity, or sedentary lifestyle, which are common in patients on maintenance hemodialysis. To overcome these confounding factors, alterations in skeletal muscle were analyzed in highly selected patients on long-term hemodialysis undergoing kidney transplantation.Design, setting, participants, & measurementsIn total, 22 patients on long-term hemodialysis scheduled for kidney transplantation with few comorbidities, but with a long-term uremic milieu exposure, and 22 age, sex, and physical activity level frequency-matched control participants were recruited. We compared biochemical, functional, and molecular characteristics of the skeletal muscle using maximal voluntary force and endurance of the quadriceps, 6-minute walking test, and muscle biopsy of vastus lateralis. For statistical analysis, mean comparison and multiple regression tests were used.ResultsIn patients on long-term hemodialysis, muscle endurance was lower, whereas maximal voluntary force was not significantly different. We observed a transition from type I (oxidative) to type II (glycolytic) muscle fibers, and an alteration of mitochondrial structure (swelling) without changes in DNA content, genome replication (peroxisome proliferator activator receptor γ coactivator-1α and mitochondrial transcription factor A), regulation of fusion (mitofusin and optic atrophy 1), or fission (dynamin-related protein 1). Notably, there were autophagosome structures containing glycogen along with mitochondrial debris, with a higher expression of light chain 3 (LC3) protein, indicating phagophore formation. This was associated with a greater conversion of LC3-I to LC3-II and the expression of Gabaralp1 and Bnip3l genes involved in mitophagy.ConclusionsIn this highly selected long-term hemodialysis population, a low oxidative phenotype could be defined by a poor endurance, a fiber-type switch, and an alteration of mitochondria structure, without evidence of sarcopenia. This phenotype could be related to uremia through the activation of autophagy/mitophagy.Clinical Trial registration numbers:NCT02794142 and NCT02040363.

Muscle Abnormalities with Kidney Failure

“…The reduced energy production is accompanied by increased formation of reactive oxygen species, which has detrimental effects in muscle, leading to a vicious circle inhibiting bioenergetic processes and enhancing apoptotic processes. In line with the findings of Souweine et al (4), autophagy and mitophagy appear to be important features of uremic myopathy. Upregulation of proteins associated with autophagy has been found in animal experiments.…”

“…In summary, the study by Souweine et al (4) reveals some specific features of muscle abnormalities in selected patients on long-term hemodialysis without apparent comorbid factors affecting muscle composition. In spite of maintained muscle mass and strength, the described phenotype with a relative reduction of oxidative type 1 fibers and loss of mitochondria explain at least in part the low endurance capacity encountered in this group.…”

“…The study by Souweine et al (4), in this issue of CJASN , aims to elucidate some effects of uremic toxicity per se on muscle morphology and function. By selecting a group of patients on long-term hemodialysis without other factors affecting muscle function, such as comorbidities and wasting, specific uremia-related effects on muscle function and morphology were evaluated.…”

The frequency of sarcopenia has increased in patients with glomerulonephritis

“…may affect muscle production in response to anabolic stimuli in the body 29 . One study reported cyclosporine reduced mitochondrial activity in skeletal muscle cells in mice 30 . In another study, it was concluded that tacrolimus causes deterioration in the regulation of skeletal muscle mass because of increasing energy use by accelerating the metabolism 31 .…”

Uremic Myopathy and Mitochondrial Dysfunction in Kidney Disease

“…In a recent cohort of fit subjects on maintenance dialysis awaiting kidney transplantation, skeletal muscle studies demonstrated preserved muscle fiber cross-sectional area, and no increase in sarcopenia, despite lower endurance capacity compared to controls. Fiber typing studies of vastus lateralis muscle in the same cohort demonstrated a lower percentage of MyHC type I fibers with higher percentage of other MyHC fibers, reflecting a switch from slow to fast fiber type [ 33 ]. On the other hand, in a similar study by Lewis et al [ 34 ], on vastus lateralis muscle biopsies of subjects on maintenance dialysis, there was a small but significant increase in type I fibers with a small decrease in IIx fibers.…”