Muscle fibrosis and maladaptation occur progressively in CKD and are rescued by dialysis

Abstract

BACKGROUND Skeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively affects physical function. Emphasis in CKD has historically been placed on muscle fiber–intrinsic deficits, such as altered protein metabolism and atrophy. However, targeted treatment of fiber-intrinsic dysfunction has produced limited improvement, whereas alterations within the fiber-extrinsic environment have scarcely been examined. METHODS We investigated alterations to the skeletal muscle interstitial environment with deep cellular phenotyping of biopsies from patients with CKD and age-matched controls and performed transcriptome profiling to define the molecular underpinnings of CKD-associated muscle impairments. We examined changes in muscle maladaptation following initiation of dialysis therapy for kidney failure. RESULTS Patients with CKD exhibited a progressive fibrotic muscle phenotype, which was associated with impaired regenerative capacity and lower vascular density. The severity of these deficits was strongly associated with the degree of kidney dysfunction. Consistent with these profound deficits, CKD was associated with broad alterations to the muscle transcriptome, including altered ECM organization, downregulated angiogenesis, and altered expression of pathways related to stem cell self-renewal. Remarkably, despite the seemingly advanced nature of this fibrotic transformation, dialysis treatment rescued these deficits, restoring a healthier muscle phenotype. Furthermore, after accounting for muscle atrophy, strength and endurance improved after dialysis initiation. CONCLUSION These data identify a dialysis-responsive muscle fibrotic phenotype in CKD and suggest the early dialysis window presents a unique opportunity of improved muscle regenerative capacity during which targeted interventions may achieve maximal impact. TRIAL REGISTRATION NCT01452412 FUNDING NIH, NIH Clinical and Translational Science Awards (CTSA), and Einstein-Mount Sinai Diabetes Research Center

Effects of counteracting measures on muscle contraction determinants in CKD: what muscle biopsy studies tell us?

“…However, in the study of Molsted et al 2015 (21) there were not reported in parallel alterations of SC and myonuclear content nor any alterations in fibers CSAs. It should be also mentioned that a recent study by Brightwell et al (19) found that the distance between capillaries and satellite cells in vastus lateralis muscle biopsies of CKD patients (dialysis and non-dialysis) was significantly greater compared to control muscle biopsies indicating impaired SC activity and function in CKD patients.…”

“…Moreover, it should be stated that the focus of the interventional studies of this review were not always skeletal muscle per se and the assessed muscle contraction determinants were mainly limited to cross sectional areas, fiber type alterarations, capillaries and mitochondrial markers. However, there is evidence that skeletal muscle of CKD patients presents with a number of additional abnormalities such as oxidative/nitrosative stress (14,15), inflammation (16,17), fat accumulation/infiltration (16,17) and fibrosis (18,19) which can also affect muscle contraction. Therefore, in order to better understand the effects of interventional studies on skeletal muscle of CKD patients, future studies should examine their effects on those parameters as well.…”

“…However, muscle specific factors such as fiber atrophy (8–10), fiber type alterations (11) and abnormalities in mitochondrial form and function (12,13), have been reported in muscle biopsies of CKD patients and can negatively affect muscle contraction. Recent studies have also reported additional muscle abnormalities at the muscle biopsy level including oxidative/nitrosative stress (14,15), inflammation (16,17), fat accumulation/infiltration (16,17) and fibrosis (18,19) which may also affect muscle contraction. Moreover, a previous study from our group (20) in an animal model of CKD, reported that muscle dysfunction of single muscle fibers, is not fully explained by atrophy (11% smaller fiber areas compared to control fibers).…”

Depressed Protein Synthesis and Anabolic Signaling Potentiate ACL Tear–Resultant Quadriceps Atrophy

“…The homogenate was used to isolate total RNA in accordance with manufacturer guidelines (Direct-zol RNA Miniprep Kit; Zymo). 5 RNA content, purity, and integrity were quantified with the 2100 Bioanalyzer (RIN > 8.1; Agilent) and the NanoDrop 2000 (Thermo Fisher) at the University of Kentucky Genomics Core.…”

“…Raw FASTQ files underwent prealignment quality control, were aligned with the STAR aligner (reference genome, GRCh38/hg38) in Partek Flow, and analyzed to obtain differential gene expression using DESeq2 (differential gene expression analysis; minimum read cutoff, 50). 5 Differential gene expression was calculated comparing ACL-injured and healthy samples. Raw P values were adjusted for multiple testing via the Benjamini-Hochberg false discovery rate (FDR) step-up method.…”