NF-κB Signaling: A Tale of Two Pathways in Skeletal Myogenesis

Abstract

NF-kappaB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-kappaB is controlled by an IkappaB kinase (IKK) complex that can direct either canonical (classical) NF-kappaB signaling by degrading the IkappaB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-kappaB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-kappaB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-kappaB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-kappaB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-kappaB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.

Effects of gender-specific adult bovine serum on myogenic satellite cell proliferation, differentiation and lipid accumulation

“…Biotinidase precursor has also been reported in skeletal muscle in bovine (Sadkowski et al, 2009). Similarly, role of NFk-β 105 subunit in skeletal muscle myogenesis has been defined as a negative regulator of proliferation (Bakkar et al, 2010). DIP2 disco interacting protein 2 homolog C like gene up-regulated in C-MS treated cells is a novel finding.…”

Untitled

“…NF-κB is a ubiquitously expressed transcription factor that is considered vital to numerous cellular processes [3,22]. It has been suggested that NF-κB directly modifies hundreds of gene products, including genes that encode cytokines, chemokines, cell adhesion molecules, growth factors, immunoregulatory receptors, acute-phase and stress response proteins, cell surface receptors, transcription factors, and several enzymes involved in protein degradation by the ubiquitin-proteasome system, as well as regulators of redox status, apoptosis, disuse atrophy, and host defense [5,23].…”

“…This is summarized in Figure 1. The NF-κB family is comprised of five genes that code for protein subunits, RelA/ p65, RelB, c-Rel, p50, and p52, which can be seen in Figure 2A [ 3,5,13,22]. In humans, the proto-oncogene c-Rel is a protein that is encoded by the REL gene (v-rel avian reticuloendotheliosis viral oncogene homolog).…”

“…The c-Rel protein is a member of the NF-κB family of transcription factors and contains a Rel homology domain (RHD) at its N-terminus and two C-terminal trans activation domains. As can be seen in Figure 2B, the IκB family consists of seven proteins including IκBα, IκBβ, IκBε, IκBγ, B-cell lymphoma 3-encoded protein (BCL-3), and precursor proteins p100 and p105 [5,13,22,24]. The most commonly described forms of NF-κB are the p50/p65 heterodimer and p50/p50 homodimer complexes, followed by p50/c-Rel and p52/RelB [3,10].…”

“…The most commonly described forms of NF-κB are the p50/p65 heterodimer and p50/p50 homodimer complexes, followed by p50/c-Rel and p52/RelB [3,10]. Unlike the other genes, p50 and p52 genes lack transcriptional activation domains, which generates p50 and p52 homodimers that function as gene repressors by blocking DNA consensus sites, which can be seen in Figure 3 [3,5,7,22].…”