Nuclear factor-κB signalling and transcriptional regulation in skeletal muscle atrophy

Abstract

The nuclear factor-κB (NF-κB) signalling pathway is a necessary component of adult skeletal muscle atrophy resulting from systemic illnesses or disuse. Studies showing a role for the NF-κB pathway in muscle disuse include unloading, denervation and immobilization, and studies showing a role for NF-κB in systemic illnesses include cancer, chronic heart failure and acute septic lung injury. Muscle atrophy due to most of these triggers is associated with activation of NF-κB transcriptional activity. With the exception of muscle unloading, however, there is a paucity of data on the NF-κB transcription factors that regulate muscle atrophy, and little is known about which genes are targeted by NF-κB transcription factors during atrophy. Interestingly, in some cases it appears that the amelioration of muscle atrophy by genetic inhibition of NF-κB signalling proteins is due to effects that are independent of the downstream NF-κB transcription factors. These questions are prime areas for investigation if we are to understand a key component of muscle wasting in adult skeletal muscle.

Figure 1

Schematic diagram showing NF-κB signaling and transcription factors involved in muscle atrophy due to illness or to disuse. NF-κB signaling proteins are involved in the signal transduction for atrophy from the myofiber membrane and/or external milieu to activate NF-κB transcription factors which then translocate to the nucleus and bind to NF-κB responsive elements (RE) and induce atrophy gene expression. Unloading atrophy seems to involve, IKKα and IKKβ, plus a non-classical complex involving p50 and Bcl-3. NF-κB signaling proteins are red. Transcription factors p65, p50, and Bcl-3 are green, yellow, and blue, respectively.

Figure 2

Diagram showing the non-NF-κB functions of IKKα (Left panel) and IKKβ (Right panel). The two centrally depicted kinases act on a variety of substrates shown by either an arrow (substrate activated by kinase) or a “T” bar (substrate inhibited by kinase). The cellular processes affected are highlighted in an oval; yellow backgrounds are processes that are induced and blue backgrounds are processes that are inhibited by the kinase activity. Also noted are cases in where the kinase has activity inside the nucleus. The references for data in this figure are noted in the text. As can be surmised, there are several opportunities for each kinase to produce effects on muscle cell metabolism that may be independent of NF-κB transcriptional activity.