NF-kappaB signaling in skeletal muscle: prospects for intervention in muscle diseases

Abstract

Muscle remodeling is an important physiological process that promotes adaptive changes in cytoarchitecture and protein composition after exercise, aging, or disease conditions. Numerous transcription factors have been reported to regulate skeletal muscle homeostasis. NF-kappaB is a major pleiotropic transcription factor modulating immune, inflammatory, cell survival, and proliferating responses; however, its role in muscle development, physiology, and disease has just started to be elucidated. The current review article aims to summarize the literature on the role of NF-kappaB signaling in skeletal muscle pathophysiology, investigated over the last years using in vitro and more recently in vivo systems. Understanding the exact role of NF-kappaB in muscle cells will allow better therapeutic manipulations in the setting of human muscle diseases.

Fig. 1

An outline of major signaling pathways leading to NF-κB activation. The best characterized NF-κB activators include TCR signaling, TNF, TLR, LTβR, and INF-γR signaling. Activation of TNF receptor results in its trimerization and recruitment of the adaptor protein TRADD, which, in turn, interacts with TRAF2. Consequently, RIP and MEKK3 link TNF signaling to IKK activation. LPS binding to TLRs activates an intracellular signaling cascade that involves recruitment of MYD88 and IRAK, phosphorylation of TRAF6, which then signals through the TAB2–TAK1–TAB1 complex to activate the IKK complex. In peripheral T cells, T cell stimulation results in PKCθ activation, which signals via the CARMA1–BCL-10–MALT1 complex to activate the IKK complex. INF-γR1 can recruit MyD88, and through MLK3 activates p38. Convergence point for most of the above cascades is the activated IκB kinase (IKK) complex, which consists of three subunits: IKK1, IKK2, and NEMO. Upon IKK activation, IκBα is phosphorylated and degraded through the ubiquitination pathway, rendering NF-κB free to translocate to the nucleus and bind to its target genes (canonical pathway). In other cases, IKK stimulation leads to p105/p50 activation and subsequent binding of Bcl3 to the p50/p50 homodimers. The p50/p50-Bcl3 complex translocates to the nucleus and induces NF-κB dependent transcription. Some activators such as BAFF or LPS can activate the non-canonical pathway. Here, activation of NF-κB-inducing kinase (NIK) results in homodimerization of IKK1, which then phosphorylates the p100 NF-κB subunit, inducing its proteolytic processing to p52. Besides their NF-κB-dependent effects, more functions independent of the NF-κB pathway have been described for IKKs. IKK1 can phosphorylate histone H3, through interaction with the transcriptional co-activator CBP. NEMO has also the ability to translocate to the nucleus following DNA damage. Nuclear NEMO is sumoylated and then ubiquitinated, in a process that depends on ATM kinase. Then, NEMO together with ATM translocate to the cytoplasm where it activates IKK2. TCR T cell receptor, TNFR tumor necrosis factor receptor, TLR Toll-like receptor, INF-γR1: interferon-γ receptor 1, RANK receptor activator of NF-κB, PKCθ protein kinase Cθ, CARMA1 caspase-associated recruitment domain-1, BCL-10 B cell lymphoma 10, MALT1 mucosa-associated lymphoid tissue lymphoma translocation gene 1, MEKK3 MAP/ERK kinase kinase 3, RIP receptor-interacting protein, TRADD TNF receptor associated via death domain, TRAF TNF-receptor-associated factor, IRAK interleukin-1-receptor-associated kinase, MYD88 myeloid differentiation primary response gene 88, TAK1 transforming-growth-factor-β-activated kinase 1, TAB1 TAK1-binding protein 1, TAB2 TAK1-binding protein 2, ATM ataxia-telangiestasia-mutated kinase, IκB inhibitor of κB, IKK IκB kinase, NEMO NF-κB essential modulator, Ub ubiquitin, NIK NF-κB-inducing kinase, MLK3 mixed-lineage kinase 3, CBP CREB-binding protein, BCL-3 B cell lymphoma 3, TCR T cell receptor, TNF tumor necrosis factor, LTβR lymphotoxin-β receptor, INF-γR interferon-γ receptor

Fig. 2

NF-κB pathway in skeletal muscles. NF-κB binds on κB sites of the cyclin D1 promoter and regulates its transcription. Moreover, the p65/p50 heterodimer complex binds to the transcriptional repressor YY1, resulting in inhibition of skeletal myogenesis. TNF-α and TWEAK activation regulates MyoD1 expression through a p65/p50 complex. In response to TNF signaling, PW1 associates with TRAF2, induces Bax translocation in mitochondria, and through activation of caspases, leads to inhibition of muscle differentiation. TNF-α signaling is important for the activation of satellite cells during muscle regeneration, through the MAP kinase p38. Synergistic effects of TNF and INF-γ result in muscle atrophy. Stable expression of constitutively active CnA in C2C12 cells induces NF-κB activation in a TNF-α-independent mechanism. Intracellular calcium in muscle cells activates calpain 3, which induces IκBα degradation, leading to NF-κB activation and translocation into the nucleus, where it regulates expression of survival genes. Upon denervation-induced atrophy, NF-κB binds on the promoter of MuRF1. Upon unloaded-induced atrophy, complexes comprising of p50 and Bcl-3 subunits are activated and translocate into the nucleus to regulate transcription of target genes. MuRF1 Murine ring finger-1, YY1 YinYang1, PW1/Peg3 paternally expressed 3, TWEAK TNF weak inducer of apoptosis, CnA activated form of calcineurin A, Bax Bcl-2-associated X protein, TRAF2 TNF-receptor-associated factor 2, RIP receptor-interacting protein, TNFR1 tumor necrosis factor receptor 1, INF-γR1 interferon-γ receptor 1, IKK IκB kinase, NEMO NF-κB essential modulator