TWEAK and cIAP1 Regulate Myoblast Fusion Through the Noncanonical NF-κB Signaling Pathway

Abstract

The fusion of mononucleated muscle progenitor cells (myoblasts) into multinucleated muscle fibers is a critical aspect of muscle development and regeneration. We identified the noncanonical nuclear factor κB (NF-κB) pathway as a signaling axis that drives the recruitment of myoblasts into new muscle fibers. Loss of cellular inhibitor of apoptosis 1 (cIAP1) protein led to constitutive activation of the noncanonical NF-κB pathway and an increase in the number of nuclei per myotube. Knockdown of essential mediators of NF-κB signaling, such as p100, RelB, inhibitor of κB kinase α, and NF-κB-inducing kinase, attenuated myoblast fusion in wild-type myoblasts. In contrast, the extent of myoblast fusion was increased when the activity of the noncanonical NF-κB pathway was enhanced by increasing the abundance of p52 and RelB or decreasing the abundance of tumor necrosis factor (TNF) receptor-associated factor 3, an inhibitor of this pathway. Low concentrations of the cytokine TNF-like weak inducer of apoptosis (TWEAK), which preferentially activates the noncanonical NF-κB pathway, also increased myoblast fusion, without causing atrophy or impairing myogenesis. These results identify roles for TWEAK, cIAP1, and noncanonical NF-κB signaling in the regulation of myoblast fusion and highlight a role for cytokine signaling during adult skeletal myogenesis.

Proinflammatory Cytokine Tumor Necrosis Factor (TNF)-like Weak Inducer of Apoptosis (TWEAK) Suppresses Satellite Cell Self-renewal through Inversely Modulating Notch and NF-κB Signaling Pathways

“…However, we cannot rule out the possibility that higher amounts of TWEAK can also reduce the levels of MyoD in satellite cells/myoblast cultures resulting in their reduced differentiation into myogenic lineage. Indeed, we and others have previously reported that higher dosages of TWEAK (Ն100 ng/ml) destabilize the MyoD protein in C2C12 myoblasts and inhibit their differentiation (31,32,41). Furthermore, there is also a possibility that the chronic presence of even low levels of TWEAK for longer durations can inhibit both satellite cell self-renewal and differentiation.…”

“…Furthermore, there is also a possibility that the chronic presence of even low levels of TWEAK for longer durations can inhibit both satellite cell self-renewal and differentiation. Indeed, a recent study has shown that low levels of TWEAK stimulate primary myoblast fusion without affecting their proliferation or differentiation (41). Therefore, it is possible that TWEAK inhibits satellite cell self-renewal by repressing Pax7 levels and causing premature fusion of MyoD-expressing cells resulting in loss of skeletal muscle mass and regenerative capacity.…”

Smac mimetic promotes glioblastoma cancer stem-like cell differentiation by activating NF-κB

“…of three independent experiments is shown; *Po0.05; **Po0.01; ***Po0.001 activation, preferentially non-canonical NF-kB signaling, was shown to promote myoblast fusion. 37 Furthermore, IAP proteins have been implied as regulators of differentiation. For example, differentiation of human prostate epithelial cells was described to be accompanied by downregulation of cIAP1 and XIAP mRNA and protein levels.…”

Deubiquitinases in skeletal muscle atrophy

“…Previous studies in HEK293 cells have shown that USP19 can deubiquitinate and stabilize cIAP proteins (Mei et al, 2011). These proteins can promote TNFα signaling in several cell types (Varfolomeev et al, 2012) and can also inhibit myogenesis in primary muscle cells (Enwere et al, 2012). So an attractive hypothesis is that USP19 might promote muscle atrophy by stabilizing cIAPs and activating the NFκB pathway.…”