XIAP Reduces Muscle Proteolysis Induced by CKD

Abstract

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.

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“…When IAP levels are reduced this leads to caspases being activated which results in apoptotic cell death. Another IAP, XChromosomelinked IAP has been shown to be red uced in the muscle of CKD mice and in vitro in muscle cells treated with serum obtained from CKD mice [46] . The activation of autophagy is known to breakdown IAPs and lead subsequently to the induction of necr optosis.…”

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“…In earlier studies of a rodent model of CKD, we found that the low muscle mass is due in part to increased protein degradation and suppressed protein synthesis. 2,3 Recently, we identified another mechanism that contributes to the development of muscle atrophy associated with CKD, namely, there are defects in the function of muscle progenitor cells (MPCs or satellite cells) that reduce their regenerative capacity. 4,5 This adverse response is relevant to muscle wasting because MPCs are required for muscle growth, the maintenance of muscle protein synthesis, and the repair of injured muscles.…”