Activation of caspase-3 in the skeletal muscle during haemodialysis

P>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 13C(6)) Phenylalanine. Results Caspase-3 activity in the skeletal muscle was higher in ESRD patients pre-HD than in controls (24966 center dot 0 +/- 4023 center dot 9 vs. 15293 center dot 3 +/- 2120 center dot 0 units, P < 0 center dot 01) and increased further during HD (end-HD) (37666 center dot 6 +/- 4208 center dot 3 units) (P < 0 center dot 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 center dot 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.