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

Mourkioti F, Rosenthal N - J. Mol. Med. (2008)

Bottom Line: 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.Understanding the exact role of NF-kappaB in muscle cells will allow better therapeutic manipulations in the setting of human muscle diseases.

View Article: PubMed Central - PubMed

Affiliation: EMBL Mouse Biology Unit, Campus A. Buzzati-Traverso, 00015, Monterotondo-Scalo, Italy. fmourkioti@embl-monterotondo.it

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.

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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
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Fig2: 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

Mentions: In addition to the identification of transcriptional NF-κB targets, potential upstream activators of NF-κB in skeletal muscle function have been extensively studied. Different research laboratories [48–58] have analyzed the effect of TNF-α in muscles. TNF-α is also called cachectin because it was found in the urine of cancer patients who suffer from muscle cachexia [59], a syndrome characterized by extreme weight loss and body wasting. Although TNF knockout mice do not show any distinct muscle phenotype under state-stage conditions [48], when human recombinant TNF was added to proliferating myoblasts, cell fusion as well as muscle differentiation was inhibited [58]. Interestingly, TNF-α inhibition of myogenesis was mediated through repressed synthesis of MyoD at the post-transcriptional level [60]. Similarly, recent studies showed that treatment of C2C12 myoblasts with TNF-like weak inducer of apoptosis (TWEAK) resulted in NF-κB activation and degradation of MyoD protein [49]. Consistently, two downstream regulators of the TNF-α pathway, namely receptor-interacting protein 2 (RIP2) and TNF-associated factor 2 (TRAF2), also negatively regulate myogenesis [61–63] (Fig. 2).Fig. 2


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

Mourkioti F, Rosenthal N - J. Mol. Med. (2008)

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
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Related In: Results  -  Collection

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Fig2: 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
Mentions: In addition to the identification of transcriptional NF-κB targets, potential upstream activators of NF-κB in skeletal muscle function have been extensively studied. Different research laboratories [48–58] have analyzed the effect of TNF-α in muscles. TNF-α is also called cachectin because it was found in the urine of cancer patients who suffer from muscle cachexia [59], a syndrome characterized by extreme weight loss and body wasting. Although TNF knockout mice do not show any distinct muscle phenotype under state-stage conditions [48], when human recombinant TNF was added to proliferating myoblasts, cell fusion as well as muscle differentiation was inhibited [58]. Interestingly, TNF-α inhibition of myogenesis was mediated through repressed synthesis of MyoD at the post-transcriptional level [60]. Similarly, recent studies showed that treatment of C2C12 myoblasts with TNF-like weak inducer of apoptosis (TWEAK) resulted in NF-κB activation and degradation of MyoD protein [49]. Consistently, two downstream regulators of the TNF-α pathway, namely receptor-interacting protein 2 (RIP2) and TNF-associated factor 2 (TRAF2), also negatively regulate myogenesis [61–63] (Fig. 2).Fig. 2

Bottom Line: 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.Understanding the exact role of NF-kappaB in muscle cells will allow better therapeutic manipulations in the setting of human muscle diseases.

View Article: PubMed Central - PubMed

Affiliation: EMBL Mouse Biology Unit, Campus A. Buzzati-Traverso, 00015, Monterotondo-Scalo, Italy. fmourkioti@embl-monterotondo.it

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.

Show MeSH
Related in: MedlinePlus