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Role for IKK2 in muscle: waste not, want not
Michael Karin
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California, USA.
Address correspondence to: Michael Karin, Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0636, USA. Phone: (858) 534-1361; Fax: (858) 534-8158; E-mail: karinoffice@ucsd.edu.
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Published November 1, 2006 - More info
J Clin Invest. 2006;116(11):2866–2868. https://doi.org/10.1172/JCI30268.
© 2006 The American Society for Clinical Investigation
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Abstract
NF-κB is a major pleiotropic transcription factor modulating immune, inflammatory, cell survival, and proliferative responses, yet the relevance of NF-κB signaling in muscle physiology and disease is less well documented. Here we show that muscle-restricted NF-κB inhibition in mice, through targeted deletion of the activating kinase inhibitor of NF-κB kinase 2 (IKK2), shifted muscle fiber distribution and improved muscle force. In response to denervation, IKK2 depletion protected against atrophy, maintaining fiber type, size, and strength, increasing protein synthesis, and decreasing protein degradation. IKK2-depleted mice with a muscle-specific transgene expressing a local Igf-1 isoform (mIgf-1) showed enhanced protection against muscle atrophy. In response to muscle damage, IKK2 depletion facilitated skeletal muscle regeneration through enhanced satellite cell activation and reduced fibrosis. Our results establish IKK2/NF-κB signaling as an important modulator of muscle homeostasis and suggest a combined role for IKK inhibitors and growth factors in the therapy of muscle diseases.
Authors
Foteini Mourkioti, Paschalis Kratsios, Tom Luedde, Yao-Hua Song, Patrick Delafontaine, Raffaella Adami, Valeria Parente, Roberto Bottinelli, Manolis Pasparakis, Nadia Rosenthal
Transcription factor NF-κB is one of the major activators of the inflammatory response (1). In most cells, the majority of the NF-κB pool resides in the cytoplasm but undergoes rapid nuclear translocation upon activation of innate immune receptors or exposure to proinflammatory cytokines, such as TNF-α or IL-1. Nuclear translocation of NF-κB or its activation depends on degradation of specific inhibitory proteins called inhibitors of NF-κB (IκBs) via a process that requires IκB phosphorylation and polyubiquitination (2). Phosphorylation of IκBs is mediated by a specialized protein kinase complex, the IκB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK1 (also known as IKKα) and IKK2 (also known as IKKβ), and a regulatory subunit called NEMO or IKKγ (3). Gene disruption experiments have established that in most cell types, in response to most stimuli, IκB degradation and NF-κB activation are mainly dependent on IKK2 (4). Hence, targeted disruption of the IKK2 gene has been used to demonstrate its involvement in a variety of inflammatory disorders, such as multiorgan dysfunction (5), colitis-associated cancer (6), and even obesity-induced insulin resistance (7). Now, in this issue of the JCI, Mourkioti et al. (8) report on the addition of muscle degeneration and atrophy to the list of pathologies that are remarkably ameliorated upon targeted deletion of IKK2. This suggests that muscle degenerative diseases may have a common inflammatory component and thus may respond to antiinflammatory therapy.
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Mechanistic and therapeutic implications
In addition to controlling the expression of proinflammatory cytokines and enzymes involved in the production of secondary inflammatory mediators, NF-κB activates the expression of critical antiapoptotic genes (17). Thus, deletion of IKK2 or inhibition of NF-κB activation quite frequently results in increased apoptosis (and even necrosis) in cells exposed to TNF-α (18–20). Thus, the findings of Mourkioti et al. (8), as well as those of Cai et al. (12), showing that inhibition of NF-κB activation prevents muscle degeneration and myofiber death (Figure 1) are truly remarkable and raise a few interesting questions. First, which target genes mediate the induction of muscle degeneration in response to NF-κB activation? Is MuRF1 the only NF-κB target gene involved in this response, or is there a role for other NF-κB targets? For instance, NF-κB is known to regulate the expression of many chemokines (21), which may recruit inflammatory cells to sites of injury and thereby cause more tissue damage. Another puzzle is why the inhibition of NF-κB in muscle cells does not result in TNF-α–induced apoptosis as commonly observed in other NF-κB–deficient cell types.
Figure 1Denervation, 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-.
While we need to wait for further research to answer these questions, the findings of Mourkioti et al. (8) and Cai et al. (12) strongly suggest that it is necessary to evaluate the ability of NF-κB inhibition to prevent muscle degeneration in various models of muscular dystrophy and atrophy, first in mice and then in humans. Several small molecule inhibitors of NF-κB activation, either of natural origin or the products of synthetic chemistry, have been described (22). While many of them are not very specific or potent, IKK2 inhibitors (23) or effective NF-κB activation inhibitors with an unknown mechanism of action (24) have recently become available. Given the prevalence of muscle degenerative diseases and their toll on life quality as well as their major economic impact, such trials are not only justified but also badly needed.
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