Activation of an alternative NF‐ΚB pathway in skeletal muscle during disuse atrophy

Abstract

Although cytokine‐induced nuclear factor KB (NF‐ΚB) pathways are involved in muscle wasting subsequent to disease, their potential role in disuse muscle atrophy has not been characterized. Seven days of hind limb unloading led to a 10‐fold activation of an NF‐κB‐dependent reporter in rat soleus muscle but not the atrophy‐resistant extensor digitorum longus muscle. Nuclear levels of p50 were markedly up‐regulated, c‐Rel was moderately up‐regulated, Rel Β was down‐regulated, and p52 and p65 were unchanged in unloaded solei. The nuclear IΚB protein Bcl‐3 was increased. There was increased binding to an NF‐ΚB consensus oligonucleotide, and this complex bound antibodies to p50, c‐Rel, and Bcl‐3 but not other NF‐ΚB family members. Tumor necrosis factor alpha (TNF‐α) and TNF receptor‐associated factor 2 protein were moderately down‐regulated. There was no difference in p38, c‐Jun NH 2 ‐terminal kinase or Akt activity, nor were activator protein 1 or nuclear factor of activated T cell‐dependent reporters activated. Thus, whereas several NF‐ΚB family members are up‐regulated, the prototypical markers of cytokine‐induced activation of NF‐ΚB seen with disease‐related wasting are not evident during disuse atrophy. Levels of an anti‐apoptotic NF‐ΚB target, Bcl‐2, were increased fourfold whereas proapoptotic proteins Bax and Bak decreased. The evidence presented here suggests that disuse muscle atrophy is associated with activation of an alternative NF‐ΚB pathway that involves the activation of p50 but not p65.—Hunter, R. B., Stevenson, E. J., Koncarevic, A., Mitchell‐Felton, H., Essig, D. A., Kandarian, S. C. Activation of an alternative NF‐ΚB pathway in skeletal muscle during disuse atrophy. FASEB J. 16, 529–538 (2002)