IKKβ/NF-κB Activation Causes Severe Muscle Wasting in Mice

Muscle wasting is a major feature of the cachexia asso-One Joslin Place ciated with diverse pathologies such as cancer, bacte-Several cytokines have been implicated in the patho-8 Department of Pediatrics genesis of muscle wasting, most notably TNF-␣, a proin-9 Department of Physical Medicine flammatory cytokine that was originally called " cachec-and Rehabilitation tin " (Tisdale, 1997; Argiles and Lopez-Soriano, 1999). Harvard Medical School Concentrations of TNF-␣ are often elevated in the circu-Boston, Massachusetts 02115 lations of patients with sepsis or cancer, contributing to negative nitrogen balance—but, by itself, TNF-␣ may be insufficient to cause muscle wasting (Moldawer et al. been implicated as potential mediators of muscle wast-Muscle wasting accompanies aging and pathological ing or atrophy, suggesting that clinical syndromes might conditions ranging from cancer, cachexia, and diabe-involve synergistic effects of combinations of cytokines tes to denervation and immobilization. We show that (Argiles and Lopez-Soriano, 1999). activation of NF-␬B, through muscle-specific trans-Since NF-␬B in muscle is activated by disuse (Hunter genic expression of activated I␬B kinase ␤ (MIKK), et al., 2002) or sepsis (Penner et al., 2001), it might play causes profound muscle wasting that resembles clini-a role in the pathogenesis of these conditions, although cal cachexia. In contrast, no overt phenotype was seen alternative intracellular pathways including caspases upon muscle-specific inhibition of NF-␬B through ex-and JNK/AP-1 have also been shown to be activated in pression of I␬B␣ superrepressor (MISR). Muscle loss muscle by cytokines (Coletti et al., 2002; Stewart et al., was due to accelerated protein breakdown through 2004). Consistent with a role for NF-␬B, in vitro blockade ubiquitin-dependent proteolysis. Expression of the E3 inhibits protein loss in C2C12 myotubes (Li and Reid, ligase MuRF1, a mediator of muscle atrophy, was in-2000). Although detailed mechanisms of NF-␬B have creased in MIKK mice. Pharmacological or genetic been established in innate immunity, inflammation, and inhibition of the IKK␤/NF-␬B/MuRF1 pathway reversed apoptosis, its in vivo functions in muscle are unknown. muscle atrophy. Denervation-and tumor-induced mus-In cells of the immune and inflammatory systems, NF-␬B cle loss were substantially reduced and survival rates is a central integration site for proinflammatory signals and a master regulator of related target genes. Numer