XIAP reduces muscle proteolysis induced by CKD

Area of Science:

• Biochemistry
• Molecular Biology
• Physiology

Background:

• Chronic kidney disease (CKD) is associated with muscle wasting.
• Caspase-3 contributes to muscle atrophy in systemic illnesses.
• The role of X-chromosome-linked inhibitor of apoptosis protein (XIAP) in CKD-induced muscle wasting is unknown.

Purpose of the Study:

• To investigate whether XIAP modulates muscle wasting in CKD.
• To determine the effect of XIAP overexpression on protein degradation in skeletal muscle during CKD.

Main Methods:

• Overexpression of XIAP in cultured skeletal muscle cells.
• Generation of transgenic mice overexpressing human XIAP in skeletal muscle (mXIAP).
• Evaluation of muscle protein degradation, proteasome activity, and gene expression in mXIAP mice with CKD.

Main Results:

• XIAP overexpression in cultured muscle cells decreased protein degradation.
• mXIAP mice with CKD showed preserved muscle weights compared to wild-type CKD mice.
• Protein degradation, proteasome activity, and caspase-3-mediated actin cleavage were reduced in mXIAP-CKD mice.
• mRNA levels of ubiquitin-proteasome pathway components were lower in mXIAP-CKD mice.

Conclusions:

• XIAP overexpression in skeletal muscle protects against CKD-induced muscle atrophy.
• XIAP inhibits multiple aspects of protein degradation in skeletal muscle during CKD.
• Reduced ubiquitin-proteasome pathway activity contributes to the protein-sparing effects of XIAP.