Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: eCollection Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
    • Publication Information:
      Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
    • Subject Terms:
      Inflammation* ; Renal Dialysis*; Muscle Proteins/*metabolism ; Muscle, Skeletal/*metabolism ; Renal Insufficiency, Chronic/*metabolism; Adult ; Animals ; Biomarkers ; C-Reactive Protein ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Homeostasis ; Humans ; Integrin beta1/genetics ; Integrin beta1/metabolism ; Kinetics ; Male ; Mice ; Mice, Knockout ; Middle Aged ; Multivariate Analysis ; Regression Analysis ; SKP Cullin F-Box Protein Ligases/metabolism ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism
    • Abstract:
      Background: Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients.
      Methods: Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models.
      Results: Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease.
      Conclusion: These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation.
      Funding: This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.
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    • Grant Information:
      UL1 TR000445 United States TR NCATS NIH HHS; R01 DK069921 United States DK NIDDK NIH HHS; I01 CX000414 United States CX CSRD VA; K24 DK062849 United States DK NIDDK NIH HHS; R01 DK045604 United States DK NIDDK NIH HHS; K23 DK100533 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: Chronic kidney disease; Metabolism; Nephrology
    • Accession Number:
      0 (Biomarkers)
      0 (Cytokines)
      0 (Integrin beta1)
      0 (Muscle Proteins)
      0 (Tripartite Motif Proteins)
      9007-41-4 (C-Reactive Protein)
      EC 2.3.2.27 (FBXO32 protein, human)
      EC 2.3.2.27 (Fbxo32 protein, mouse)
      EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases)
      EC 2.3.2.27 (TRIM63 protein, human)
      EC 2.3.2.27 (Ubiquitin-Protein Ligases)
    • Publication Date:
      Date Created: 20171205 Date Completed: 20190708 Latest Revision: 20220330
    • Publication Date:
      20240829
    • Accession Number:
      PMC5752392
    • Accession Number:
      10.1172/jci.insight.95185
    • Accession Number:
      29202452