Mittal et al. identify a cytokine signaling pathway that induces the breakdown of disused skeletal muscle. Blocking this pathway could prevent immobilized patients from losing their muscle tissue.
Skeletal muscle wastes away when its activity is reduced by—for example—the loss of stimulatory motor neurons. Although the mechanism by which muscle fibers break down is understood fairly well, how the process is triggered remains unknown. The TNF-related cytokine TWEAK can induce muscle loss, but whether it does so in disused muscle is unclear.
Mittal et al. compared how mice expressing different amounts of TWEAK responded when the nerve innervating their hind legs was severed. Mice producing excess TWEAK lost their muscle more quickly than wild-type animals, whereas mice lacking this cytokine were largely protected from muscle breakdown. TWEAK levels also correlated with the amount of fibrosis, another common symptom of muscle disuse. Inhibiting TWEAK with a neutralizing antibody was sufficient to block muscle loss following denervation, suggesting that the pathway could be a viable therapeutic target. TWEAK signaling activated the transcription factor NF-kB to up-regulate the ubiquitin ligase MuRF-1, which targets components of the muscle thick filament for destruction.
Rather than stimulating TWEAK production, denervation increases expression of the cytokine's receptor, Fn14. The next question, says lead author Ashok Kumar, is how this receptor is up-regulated when muscle use is curtailed.