Skeletal muscle mitochondrial dysfunction is present in patients with ckd before initiation of maintenance hemodialysis

Jorge L. Gamboa, Baback Roshanravan, Theodore Towse, Chad A. Keller, Aaron M. Falck, Chang Yu, Walter R. Frontera, Nancy J. Brown, T. Alp Ikizler

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background and objectives Patients with CKD suffer from frailty and sarcopenia, which is associated with higher morbidity and mortality. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. In this study, we tested the hypothesis that mitochondrial dysfunction is associated with the severity of CKD. We also evaluated the interaction between mitochondrial function and coexisting comorbidities, such as impaired physical performance, intermuscular adipose tissue infiltration, inflammation, and oxidative stress. Design, setting, participants, & measurements Sixty-three participants were studied, including controls (n521), patients with CKD not on maintenance hemodialysis (CKD 3–5; n520), and patients on maintenance hemodialysis (n522). We evaluated in vivo knee extensors mitochondrial function using31P magnetic resonance spectroscopy to obtain the phosphocreatine recovery time constant, a measure of mitochondrial function. We measured physical performance using the 6-minute walk test, intermuscular adipose tissue infiltration with magnetic resonance imaging, and markers of inflammation and oxidative stress in plasma. In skeletal muscle biopsies from a select number of patients on maintenance hemodialysis, we also measured markers of mitochondrial dynamics (fusion and fission). Results We found a prolonged phosphocreatine recovery constant in patients on maintenance hemodialysis (53.3 [43.4–70.1] seconds, median [interquartile range]) and patients with CKD not on maintenance hemodialysis (41.5 [35.4–49.1] seconds) compared with controls (38.9 [32.5–46.0] seconds; P50.001 among groups). Mitochondrial dysfunction was associated with poor physical performance (r50.62; P50.001), greater intermuscular adipose tissue (r50.44; P50.001), and increased markers of inflammation and oxidative stress (r50.60; P50.001). We found mitochondrial fragmentation and increased content of dynamin-related protein 1, a marker of mitochondrial fission, in skeletal muscles from patients on maintenance hemodialysis (0.86 [0.48–1.35] arbitrary units (A.U.), median [interquartile range]) compared with controls (0.60 [0.24–0.75] A.U.). Conclusions Mitochondrial dysfunction is due to multifactorial etiologies and presents prior to the initiation of maintenance hemodialysis, including in patients with CKD stages 3–5.

Original languageEnglish (US)
Pages (from-to)926-936
Number of pages11
JournalClinical Journal of the American Society of Nephrology
Volume15
Issue number7
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation

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