Activation of caspase-3 in the skeletal muscle during haemodialysis.
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).


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 (13)C(6) ) 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.


CONCLUSIONS
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.
Boivin
Michel A
MA
Division of Pulmonary and Critical Care, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Battah
Shadi I
SI
Dominic
Elizabeth A
EA
Kalantar-Zadeh
Kamyar
K
Ferrando
Arny
A
Tzamaloukas
Antonios H
AH
Dwivedi
Rama
R
Ma
Thomas A
TA
Moseley
Pope
P
Raj
Dominic S C
DS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000097:blood; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000473:pathology / Q000503:physiopathology*; D010649:Phenylalanine / Q000378:metabolism; D006435:Renal Dialysis
D015850:Interleukin-6; D009124:Muscle Proteins; D010649:Phenylalanine; D053148:Caspase 3