Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients
Serpil M. Deger, … , Naji N. Abumrad, T. Alp Ikizler
Serpil M. Deger, … , Naji N. Abumrad, T. Alp Ikizler
Published November 16, 2017
Citation Information: JCI Insight. 2017;2(22):e95185. https://doi.org/10.1172/jci.insight.95185.
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Clinical Research and Public Health Metabolism Nephrology

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

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.

Authors

Serpil M. Deger, Adriana M. Hung, Jorge L. Gamboa, Edward D. Siew, Charles D. Ellis, Cindy Booker, Feng Sha, Haiming Li, Aihua Bian, Thomas G. Stewart, Roy Zent, William E. Mitch, Naji N. Abumrad, T. Alp Ikizler

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Figure 6

The analysis of cytokines and tissue markers of protein homeostasis in CKD mice and controls.

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The analysis of cytokines and tissue markers of protein homeostasis in C...
Serum cytokines (A), relative protein expression by immunoblot (B) and relative mRNA expression by real-time PCR (C and D) are depicted for WT (n = 6), HoxB7 Cre mice (Hom-Hox, n = 6) and mice lacking β1 integrin in the podocytes (Hom-Pod, n = 6). Parameters are presented as mean ± SEM. There were numerical differences in serum concentrations of serum IL-6, IL-10, and TNF-α between groups although none of these differences reached statistical significance (A). There was an overall statistically significant difference between groups when comparing 20S proteasome subunits (P = 0.01) but not with Ubiquitin (Ub) conjugates and pAKT by immunoblotting (P = 0.49 and P = 0.11, respectively). In group comparisons (B), Ub-conjugates, 20S proteasome subunits, and pAKT were highly statistically significantly elevated in Hom-Pod mice compared with WT or Hom-Hox mice (P < 0.003 for all). There were no statistically significant differences in Ub, 20S proteasome subunits, and pATK when comparing Hom-Hox mice versus WT mice (P > 0.0125 for all).