IKK/NF-κB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis

Bakkar, Nadine; Wang, Jingxin; Ladner, Katherine J.; Wang, Huating; Dahlman, Jason M.; Carathers, Micheal; Acharyya, Swarnali; Rudnicki, Michael A.; Hollenbach, Andrew D.; Guttridge, Denis C.

doi:10.1083/jcb.200707179

Cited by 191 publications

(168 citation statements)

References 67 publications

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“…Consistent with the findings above, analysis of muscles from newborn p65 Ϫ/Ϫ mice (which were maintained on a TNF␣ background to circumvent p65 null lethality and from here on referred to only as p65 Ϫ/Ϫ mice) (27) revealed a significant increase in the total number of myofibers (25). This phenotype suggested that the inhibitory myogenic activity of NF-B is present in the early phases of postnatal muscle development.…”

supporting

confidence: 69%

“…In contrast to previous findings where we demonstrated that the absence of p65 in primary myoblasts or silencing of p65 by siRNA in C2C12 myoblasts caused myotube formation to be enhanced (25), here in this co-culture system the total number of myotubes remained the same (supplemental Fig. 4), arguing that fibroblast-derived NF-B activity is responsible for regulating myoblast fusion but is not involved in controlling myogenesis.…”

Section: Nf-b Regulates Inos Expression Within Stromal Fibroblasts Ofcontrasting

confidence: 55%

“…Recent findings have illustrated the ability of NF-B to function as an inhibitor of skeletal myogenesis (19,24,25). The purpose of this study was to characterize the role of NF-B during early postnatal muscle development.…”

Section: Discussionmentioning

confidence: 99%

“…iNOS Ϫ/Ϫ and wild type CD2 and C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Cell Culture-C2C12 myoblasts, mouse embryonic fibroblasts (MEFs), and primary myoblasts were cultured as previously described (25). Primary fibroblasts were isolated according to the myoblast purification pre-plating steps as described by Rando and Blau (32).…”

Section: Methodsmentioning

confidence: 99%

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NF-κB Functions in Stromal Fibroblasts to Regulate Early Postnatal Muscle Development

Dahlman

Bakkar

et al. 2010

Journal of Biological Chemistry

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Classical NF-B activity functions as an inhibitor of the skeletal muscle myogenic program. Recent findings reveal that even in newborn RelA/p65 ؊/؊ mice, myofiber numbers are increased over that of wild type mice, suggesting that NF-B may be a contributing factor in early postnatal skeletal muscle development. Here we show that in addition to p65 deficiency, repression of NF-B with the IB␣-SR transdominant inhibitor or with muscle-specific deletion of IKK␤ resulted in similar increases in total fiber numbers as well as an up-regulation of myogenic gene products. Upon further characterization of early postnatal muscle, we observed that NF-B activity progressively declines within the first few weeks of development. At birth, the majority of this activity is compartmentalized to muscle fibers, but by neonatal day 8 NF-B activity from the myofibers diminishes, and instead, stromal fibroblasts become the main cellular compartment within the muscle that contains active NF-B. We find that NF-B functions in these fibroblasts to regulate inducible nitric-oxide synthase expression, which we show is important for myoblast fusion during the growth and maturation process of skeletal muscle. Together, these data broaden our understanding of NF-B during development by showing that in addition to its role as a negative regulator of myogenesis, NF-B also regulates nitric-oxide synthase expression within stromal fibroblasts to stimulate myoblast fusion and muscle hypertrophy.

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supporting

confidence: 69%

Section: Nf-b Regulates Inos Expression Within Stromal Fibroblasts Ofcontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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NF-κB Functions in Stromal Fibroblasts to Regulate Early Postnatal Muscle Development

Dahlman

Bakkar

et al. 2010

Journal of Biological Chemistry

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“…For example, at 48h after acute liver injury in mice, MΦs simultaneously express IL-10 and TNF. During skeletal muscle repair, satellite cells are major targets of TNFα signaling that promotes the early proliferative stage of myogenesis [43]. In the case of heart, TNFα has a cardioprotective function in mice [44].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

Kudlik

Hegyi

Czibula

et al. 2016

Experimental Cell Research

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Mechanisms of Muscle Injury, Repair, and Regeneration

Tidball

2011

Comprehensive Physiology

335

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Skeletal muscle continuously adapts to changes in its mechanical environment through modifications in gene expression and protein stability that affect its physiological function and mass. However, mechanical stresses commonly exceed the parameters that induce adaptations, producing instead acute injury. Furthermore, the relatively superficial location of many muscles in the body leaves them further vulnerable to acute injuries by exposure to extreme temperatures, contusions, lacerations or toxins. In this article, the molecular, cellular, and mechanical factors that underlie muscle injury and the capacity of muscle to repair and regenerate are presented. Evidence shows that muscle injuries that are caused by eccentric contractions result from direct mechanical damage to myofibrils. However, muscle pathology following other acute injuries is largely attributable to damage to the muscle cell membrane. Many feaures in the injury-repair-regeneration cascade relate to the unregulated influx of calcium through membrane lesions, including: (i) activation of proteases and hydrolases that contribute muscle damage, (ii) activation of enzymes that drive the production of mitogens and motogens for muscle and immune cells involved in injury and repair, and (iii) enabling protein-protein interactions that promote membrane repair. Evidence is also presented to show that the myogenic program that is activated by acute muscle injury and the inflammatory process that follows are highly coordinated, with myeloid cells playing a central role in modulating repair and regeneration. The early-invading, proinflammatory M1 macrophages remove debris caused by injury and express Th1 cytokines that play key roles in regulating the proliferation, migration, and differentiation of satellite cells. The subsequent invasion by anti-inflammatory, M2 macrophages promotes tissue repair and attenuates inflammation. Although this system provides an effective mechanism for muscle repair and regeneration following acute injury, it is dysregulated in chronic injuries. In this article, the process of muscle injury, repair and regeneration that occurs in muscular dystrophy is used as an example of chronic muscle injury, to highlight similarities and differences between the injury and repair processes that occur in acutely and chronically injured muscle.

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IKK/NF-κB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis

Cited by 191 publications

References 67 publications

NF-κB Functions in Stromal Fibroblasts to Regulate Early Postnatal Muscle Development

NF-κB Functions in Stromal Fibroblasts to Regulate Early Postnatal Muscle Development

Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

Mechanisms of Muscle Injury, Repair, and Regeneration

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