Skeletal Muscle Mitochondrial Dysfunction Is Present in Patients with CKD before Initiation of Maintenance Hemodialysis

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 ( n =21), patients with CKD not on maintenance hemodialysis (CKD 3–5; n =20), and patients on maintenance hemodialysis ( n =22). We evaluated in vivo knee extensors mitochondrial function using 31 P 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; P =0.001 among groups). Mitochondrial dysfunction was associated with poor physical performance ( r =0.62; P =0.001), greater intermuscular adipose tissue ( r =0.44; P =0.001), and increased markers of inflammation and oxidative stress ( r =0.60; P =0.001). 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.