XIAP reduces muscle proteolysis induced by CKD.
X-chromosome-linked inhibitor of apoptosis protein (XIAP) is an endogenous caspase inhibitor. Caspase-3 contributes to the muscle wasting associated with chronic kidney disease (CKD) and other systemic illnesses, but whether XIAP modulates muscle wasting in CKD is unknown. Here, overexpression of XIAP in cultured skeletal muscle cells decreased protein degradation induced by serum deprivation, suggesting that caspase-mediated proteolysis contributes to muscle atrophy. We generated transgenic mice that overexpress human XIAP specifically in skeletal muscle (mXIAP) and evaluated muscle protein degradation induced by CKD. mXIAP mice with normal kidney function exhibited mild skeletal muscle hypertrophy. Muscle weights of mXIAP mice with CKD (mXIAP-CKD) were indistinguishable from wild-type mice, suggesting that overexpression of XIAP in skeletal muscle protects from CKD-induced muscle atrophy. The rate of total protein degradation, proteasome chymotrypsin-like activity, and caspase-3-mediated actin cleavage all were lower in muscle isolated from mXIAP-CKD mice compared with wild-type CKD mice. Concomitant with the reduction in overall proteolysis, mRNA levels of ubiquitin, muscle-specific ring finger 1, and atrogin-1/muscle atrophy F-box were lower in mXIAP-CKD mice, suggesting that decreased expression of the ubiquitin-proteasome pathway components may contribute to the protein-sparing effects of XIAP. In summary, these results demonstrate that XIAP inhibits multiple aspects of protein degradation in skeletal muscle during CKD.
Hu
Junping
J
Renal Division, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Du
Jie
J
Zhang
Liping
L
Price
S Russ
SR
Klein
Janet D
JD
Wang
Xiaonan H
XH
D000199:Actins / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D061945:Caspase Inhibitors; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex