Activation of caspase-3 in the skeletal muscle during haemodialysis

• Published in: European journal of clinical investigation Vol. 40; no. 10; pp. 903 - 910
• Main Authors: Boivin, Michel A., Battah, Shadi I., Dominic, Elizabeth A., Kalantar-Zadeh, Kamyar, Ferrando, Arny, Tzamaloukas, Antonios H., Dwivedi, Rama, Ma, Thomas A., Moseley, Pope, Raj, Dominic S. C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2010; Wiley-Blackwell
• Subjects: Adult; Aged; Aged, 80 and over; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Case-Control Studies; Caspase 3 - metabolism; Emergency and intensive care: renal failure. Dialysis management; end-stage renal disease; General aspects; Humans; inflammation; Intensive care medicine; interleukin-6; Interleukin-6 - metabolism; Kidney Failure, Chronic - blood; Medical sciences; Middle Aged; Muscle Proteins - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular Atrophy - pathology; Muscular Atrophy - physiopathology; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Phenylalanine - metabolism; proteolysis; Renal Dialysis; Renal failure; ubiquitin; Kidney disease; Human; Ubiquitin; Urinary system disease; Chronic renal failure; Enzyme; Hemodialysis; Cysteine endopeptidases; Cytokine; Terminal stage; Activation; Inflammation; Striated muscle; end-stage renal disease; interleukin-6; Interleukin 6; Medicine; Extrarenal dialysis; Peptidases; Cell death; Proteolysis; Renal failure; Hydrolases; Apoptosis
• DOI: 10.1111/j.1365-2362.2010.02347.x
• ISSN: 0014-2972; 1365-2362

Eur J Clin Invest 2010; 40 (10): 903–910 Background and Objective  Muscle atrophy in end‐stage renal disease (ESRD) may be due to the activation of apoptotic and proteolytic pathways. We hypothesized that activation of caspase‐3 in the skeletal muscle mediates apoptosis and proteolysis during haemodialysis (HD). Materials and Methods  Eight ESRD patients were studied before (pre‐HD) and during HD and the findings were compared with those from six healthy volunteers. Protein kinetics was determined by primed constant infusion of L‐(ring 13C6) Phenylalanine. Results  Caspase‐3 activity in the skeletal muscle was higher in ESRD patients pre‐HD than in controls (24966·0 ± 4023·9 vs. 15293·3 ± 2120·0 units, P < 0·01) and increased further during HD (end‐HD) (37666·6 ± 4208·3 units) (P < 0·001). Actin fragments (14 kDa) generated by caspase‐3 mediated cleavage of actomyosin was higher in the skeletal muscle pre‐HD (68%) and during HD (164%) compared with controls. The abundance of ubiquitinized carboxy‐terminal actin fragment was also significantly increased during HD. Skeletal muscle biopsies obtained at the end of HD exhibited augmented apoptosis, which was higher than that observed in pre‐HD and control samples (P < 0·001). IL‐6 content in the soluble fraction of the muscle skeletal muscle was increased significantly during HD. Protein kinetic studies showed that catabolism was higher in ESRD patients during HD compared with pre‐HD and control subjects. Muscle protein catabolism was positively associated with caspase‐3 activity and skeletal muscle IL‐6 content. Conclusion  Muscle atrophy in ESRD may be due to IL‐6 induced activation of caspase‐3 resulting in apoptosis as well as muscle proteolysis during HD.