NF-κB Promotes Muscle Wasting in Transgenic Mice

Abstract

Muscle wasting is a serious complication of several human diseases, including diabetes, cancer, sepsis, and AIDS. Previous work implicated activation of the transcription factor nuclear factor-κB (NF-κB) in protein loss in cultured myotubes. Cai et al . created transgenic mice in which NF-κB was excessively activated [MIKK (muscle-specific expression of IKK, which is the kinase that phosphorylates the inhibitor, IκB, thus allowing activation of NF-κB) mice] or repressed [MISR (muscle-specific expression of IκB superrepressor) mice], specifically in skeletal muscle. The MIKK mice exhibited profound muscle loss, and crossing the MIKK mice to the MISR mice reversed this phenotype. Several parameters indicated that muscle loss in the MIKK mice was due to increased catabolism of muscle proteins: high circulating and excreted amounts of protein breakdown products, high oxygen consumption and heat production, and high protein turnover in ex vivo assays. Furthermore, gene microarray analysis indicated that the MIKK mice had increased expression of genes encoding proteins implicated in protein ubiquitination and proteasomal degradation, including the muscle-specific ubiquitin ligase MuRF1. Crossing the MIKK mice to MuRF —/— mice showed partial rescue of the muscle-wasting phenotype of the MIKK mice. MISR mice showed resistance to muscle loss caused by either denervation or injection of Lewis lung carcinoma cells. Neither the MISR nor the MIKK mice exhibited any changes compared with wild-type mice in insulin sensitivity when fed a normal or high-fat diet. These mice reveal that the NF-κB is clearly responsible for at least one pathway that leads to muscle wasting but does not appear to be a central regulator of insulin sensitivity in muscle. D. Cai, J. D. Frantz, N. E. Tawa Jr., P. A. Melendez, B.-C. Oh, H. G. W. Lidov, P.-O. Hasselgren, W. R. Frontera, J. Lee, D. J. Glass, S. E. Shoelson, IKKβ/NF-κB activation causes severe muscle wasting in mice. Cell 119 , 285-298 (2004). [Online Journal]