Understanding Atrophy

Science Signaling  04 Jan 2011:
Vol. 4, Issue 154, pp. ec3
DOI: 10.1126/scisignal.4154ec3

Skeletal muscle atrophy is a major health concern and can be caused by denervation, immobility, or chronic disease states, such as diabetes and cancer. Previous work had found that the denervated muscles were more responsive to the cytokine TWEAK, and the same group now reports that the scaffold and ubiquitin ligase TRAF6 is involved in the activation of various signaling molecules implicated in muscle atrophy, including c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), AMP-activated protein kinase (AMPK), and nuclear factor κB (NF-κB). TRAF6 was abundant in undifferentiated myoblasts (C2C12) and in developing skeletal muscle of young mice, but its abundance decreased in differentiated myotubes (C2C12 cells) and in adult mice. In multiple paradigms that cause muscle atrophy (denervation or mouse models of cancer-induced cachexia or diabetes), TRAF6 transcription, protein abundance, and ubiquitylation increased in the atrophying muscles. Although muscle-specific knockout of TRAF6 did not cause any overt muscle phenotypes, muscle atrophy due to denervation was mostly prevented by TRAF6 depletion, on the basis of muscle mass, histology, force production, and specific protein degradation. In response to denervation or the model of cancer-induced cachexia, TRAF6-depleted muscles also showed significantly less or no transcriptional induction of genes encoding two ubiquitin ligases implicated in muscle atrophy, as well as of genes encoding proteins involved in autophagy. Denervation caused less activation of NF-κB, JNK, AMPK, and p38 MAPK in TRAF6-depleted muscles. Finally, the activation of NF-κB in TRAF6-knockout mouse embryo fibroblasts by TWEAK was mostly abolished, which suggests that TRAF6 is likely to link this atrophy-inducing cytokine to downstream signaling pathways.

P. K. Paul, S. K. Gupta, S. Bhatnagar, S. K. Panguluri, B. G. Darnay, Y. Choi, A. Kumar, Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice. J. Cell Biol. 191, 1395–1411 (2010). [Abstract] [Full Text]