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

Camille R Brightwell, Ameya S Kulkarni, William Paredes, Kehao Zhang, Jaclyn B Perkins, Knubian J Gatlin, Matthew Custodio, Hina Farooq, Bushra Zaidi, Rima Pai, Rupinder S Buttar, Yan Tang, Michal L Melamed, Thomas H Hostetter, Jeffrey E Pessin, Meredith Hawkins, Christopher S Fry, Matthew K Abramowitz, Camille R Brightwell, Ameya S Kulkarni, William Paredes, Kehao Zhang, Jaclyn B Perkins, Knubian J Gatlin, Matthew Custodio, Hina Farooq, Bushra Zaidi, Rima Pai, Rupinder S Buttar, Yan Tang, Michal L Melamed, Thomas H Hostetter, Jeffrey E Pessin, Meredith Hawkins, Christopher S Fry, Matthew K Abramowitz

Abstract

BACKGROUNDSkeletal 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.METHODSWe 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.RESULTSPatients 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.CONCLUSIONThese 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 REGISTRATIONNCT01452412FUNDINGNIH, NIH Clinical and Translational Science Awards (CTSA), and Einstein-Mount Sinai Diabetes Research Center.

Keywords: Chronic kidney disease; Extracellular matrix; Muscle Biology; Nephrology; Skeletal muscle.

Figures

Figure 1. Flow diagram of study participation.
Figure 1. Flow diagram of study participation.
ESRD indicates dialysis patients (transplant patients were not recruited).
Figure 2. Collagen content and density are…
Figure 2. Collagen content and density are progressively elevated in skeletal muscle of patients with CKD.
Proportion of ECM collagen content is elevated in CKD patients (A) and negatively associated with eGFR (B) (n = 33). Densely packed collagen content is elevated in CKD patients (C) and negatively associated with eGFR (D) (n = 33). Loosely packed collagen content was numerically higher but not significantly different in CKD patients (E) and not significantly correlated with eGFR (F) (n = 33). Representative images of picrosirius red staining in control and CKD muscle under both bright-field and polarized light (G). Total skeletal muscle collagen content assayed biochemically is elevated in CKD patients (H) and negatively associated with GFR (I) (n = 28). Comparisons made using 2-tailed t tests or Wilcoxon rank-sum tests. Spearman coefficients calculated to test correlations. Scale bar: 100 μm. *P < 0.05, control compared with CKD.
Figure 3. Satellite cell abundance, proximity of…
Figure 3. Satellite cell abundance, proximity of satellite cells to capillaries, and capillary density are lower in skeletal muscle of patients with CKD.
Satellite cell abundance is lower in CKD patients (A) and positively associated with eGFR (B) (n = 35). Representative images of satellite cell and capillary staining (C). Satellite cell activation is numerically, but not statistically, elevated in patients with stage 3 CKD only (D) and not associated with eGFR (E) (n = 34). Representative images of activated satellite cell staining (F). The distance between satellite cells and nearest capillary is elevated in subjects with CKD (G) and negatively associated with eGFR (H) (n = 32). CFPE, an index of capillary density and blood-muscle exchange, is lower in subjects with CKD (I) and positively associated with eGFR (J) (n = 27). Comparisons made using 2-tailed t tests or Wilcoxon rank-sum tests. Spearman coefficients calculated to test correlations. Scale bar: 100 μm. *P < 0.05, control compared with CKD.
Figure 4. Transcriptomic differences in skeletal muscle…
Figure 4. Transcriptomic differences in skeletal muscle of patients with CKD reveal alteration of genes within angiogenic and fibrotic pathways and rescue of Myc and interferon pathways postdialysis.
Volcano plot highlighting global gene expression differences in CKD versus control (A). Heatmap with the top 100 differentially expressed genes in CKD (B). Orange bar, CKD; purple bar, control. Genes involved in VEGF signaling, ECM organization, and collagen formation are downregulated in CKD (C). Heatmaps of genes belonging to VEGF (D), ECM organization (E), and collagen formation (F) pathways that are differentially expressed in CKD versus control (n = 14). Orange bar, CKD; purple bar, control. GSEA plots reveal differential regulation of Myc, interferon-α, and interferon-γ pathways in CKD and rescue (change in regulation toward control values) after dialysis (G) (n = 3).
Figure 5. Dialysis rescues pathological phenotype in…
Figure 5. Dialysis rescues pathological phenotype in skeletal muscle associated with CKD.
ECM collagen content (A) (n = 32), densely packed collagen (B) (n = 31), loosely packed collagen (C) (n = 31), and total muscle collagen assayed biochemically (D) (n = 29) are lower in subjects who have undergone dialysis compared with patients with advanced CKD. Total satellite cell abundance (E) (n = 33), the distance between satellite cells and their nearest capillary (F) (n = 31), and the CFPE ratio (G) (n = 27) are altered in patients who have undergone dialysis compared with those with advanced CKD, with a restoration toward control values. Data in A–G include only control, CKD stage 4/5, and dialysis patients. CKD stages 4/5 represent a subset of total CKD patients as presented in Figures 1 and 2 who have an eGFR < 30 mL/min/1.73 m2. Comparisons made using mixed effects models. Satellite cell abundance is negatively associated with densely packed collagen content (H) (n = 37). Spearman coefficient calculated to test correlation. *P < 0.05 compared with CKD stages 4/5. #P < 0.05 compared with control.

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