Role for IKK2 in muscle: waste not, want not

Abstract

Activation of transcription factor NF-kappaB, the major regulator of the inflammatory response, depends on the inhibitor of NF-kappaB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK1 and IKK2 (also known as IKKalpha and IKKbeta), and a regulatory subunit, IKKgamma (also known as NEMO). In this issue of the JCI, Mourkioti et al. show that muscle-specific disruption in mice of the gene encoding IKK2 prevents NF-kappaB activation in response to denervation or toxin-induced injury (see the related article beginning on page 2945). Importantly, this genetic manipulation prevents muscle wasting, thereby providing strong evidence in support of a major pathogenic role for inflammation in a variety of muscular dystrophies characterized by progressive muscle fiber degeneration.

Figure 1. Denervation, immobilization, toxins, and cachexia (mediated by TNF-α) induce muscle degeneration and atrophy through the activation of IKK and NF-κB in muscle cells.

Once activated, NF-κB leads to upregulation of MuRF1, a ubiquitin ligase involved in degradation of muscle proteins. NF-κB activation also leads to induction of chemokines that recruit inflammatory cells, such as macrophages, that can cause further muscle damage. P, phospho-.