Markers of oxidative stress in the skeletal muscle of patients on haemodialysis.

BACKGROUND: Increased oxidative stress may play a role in morbidity and mortality of patients with renal failure. Most studies have examined serum markers of oxidation, but it is unclear whether oxidative stress is involved in skeletal muscle atrophy. METHODS: This study examined markers of oxidative stress in the skeletal muscle of 10 haemodialysed patients and 10 control subjects. Biopsies from the quadriceps femoris were analysed for reduced and oxidized glutathione, protein thiols, malonaldehyde and heat shock proteins (HSP27, HSP60 and HSP70), superoxide dismutase and catalase activities. A novel microdialysis procedure was used to examine hydroxyl radical activity in the interstitial fluid of the tibialis anterior. RESULTS: Patients had muscle atrophy with a reduced diameter of both type I and II fibres (by 15 and 20%, respectively). Muscle microdialysates contained 2,3- and 2,5-dihydroxybenzoates formed from salicylate indicating hydroxyl radical activity, with no differences between patients and control subjects. Muscle protein thiol and oxidized glutathione contents were unchanged in patients, but malonaldehyde content was reduced. In contrast, total muscle glutathione and heat shock protein contents were increased. Muscle superoxide dismutase activity was unchanged, but catalase activity was reduced in patients. CONCLUSIONS: The muscle of patients undergoing haemodialysis undergoes some adaptive responses in total glutathione content, heat shock protein content and catalase activity that are potentially related to chronic oxidative stress. However, there is no evidence of gross oxidation, nor any clear relationship between oxidative stress and muscle fibre atrophy, arguing against a direct role of oxidants in the degenerative processes.

Abnormal mitochondrial function and muscle wasting, but normal contractile efficiency, in haemodialysed patients studied non-invasively in vivo.

BACKGROUND: Muscle dysfunction, which contributes to morbidity in patients on haemodialysis, has several manifestations and a number of possible causes. We applied the non-invasive techniques of (31)P-magnetic resonance spectroscopy ((31)P-MRS), magnetic resonance imaging (MRI) and near-infrared spectroscopy (NIRS) to calf muscle of dialysed patients to define the abnormalities in muscle cross-sectional area (CSA), contractile efficiency, mitochondrial function and vascular O(2) supply. METHODS: We performed (31)P-MRS/NIRS/MRI studies on the lateral gastrocnemius during isometric plantarflexion and recovery in 23 male patients on haemodialysis (age 24-71 years; haemoglobin 9.9-14.2 g/dl; bicarbonate 17-30 mmol/l; urea reduction ratio 53-77%; parathyroid hormone 1-95 U/l) and 15 male controls (age 29-71 years). To understand the relationships between calf CSA and body mass we also performed MRI only in a further six male patients and 18 male controls. RESULTS: In patients, exercise duration was 30+/-11% lower than in controls. Muscle CSA was lower by 26+/-5%, but contractile efficiency (force/CSA/ATP turnover) was normal. Slowing of post-exercise phosphocreatine (PCr) recovery implied a 22+/-5% defect in effective 'mitochondrial capacity'. That PCr recovery was slow relative to NIRS recovery suggests that this is largely an intrinsic mitochondrial problem (not the result of impaired O(2) supply), one which, furthermore, correlated with CSA. Urea reduction ratio showed a negative correlation with body mass and CSA, but none with PCr rate constant. CONCLUSIONS: The relationships to urea reduction ratio reflect the effect of muscle mass on dialysis efficiency, rather than direct effects on muscle CSA or metabolism. The relationship between PCr recovery and calf CSA suggests a role for the mitochondrial defect, whatever its cause, in the development of muscle wasting, although a common cause (e.g. physical inactivity) for both abnormalities cannot be ruled out.