IKKβ/NF-κB Activation Causes Severe Muscle Wasting in Mice

Cai, Dongsheng; Frantz, J. Daniel; Tawa, Nicholas E.; Meléndez, Peter A.; Oh, Byung‐Chul; Lidov, Hart G.W.; Hasselgren, Per Olof; Frontera, Walter R.; Lee, Jongsoon; Glass, David J.; Shoelson, Steven E.

doi:10.1016/j.cell.2004.09.027

Cited by 1,203 publications

(1,297 citation statements)

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“…Given that these two E3 ligases can be activated through increased ROS levels (Li et al. 2003; Cai et al. , 2004), we further investigated whether Mstn induces E3 ligases in a ROS‐dependent pathway.…”

Section: Resultsmentioning

confidence: 99%

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

et al. 2011

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SummaryAbnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However, the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here, we show that myostatin (Mstn) is a pro‐oxidant and signals the generation of ROS in muscle cells. Myostatin, a transforming growth factor‐β (TGF‐β) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through tumor necrosis factor‐α (TNF‐α) signaling via NF‐κB and NADPH oxidase. Aged Mstn null (Mstn−/−) muscles, which display reduced sarcopenia, also show an increased basal antioxidant enzyme (AOE) levels and lower NF‐κB levels indicating efficient scavenging of excess ROS. Additionally, our results indicate that both TNF‐α and hydrogen peroxide (H2O2) are potent inducers of Mstn and require NF‐κB signaling for Mstn induction. These results demonstrate that Mstn and TNF‐α are components of a feed forward loop in which Mstn triggers the generation of second messenger ROS, mediated by TNF‐α and NADPH oxidase, and the elevated TNF‐α in turn stimulates Mstn expression. Higher levels of Mstn in turn induce muscle wasting by activating proteasomal‐mediated catabolism of intracellular proteins. Thus, we propose that inhibition of ROS induced by Mstn could lead to reduced muscle wasting during sarcopenia.

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Section: Resultsmentioning

confidence: 99%

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

et al. 2011

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“…Mice with muscle‐specific transgenic expression of activated IKK β have profound muscle wasting due to the activation of NF‐ κ B/MuRF (Cai et al. 2004). Muscle wasting in these mice was completely blocked by muscle‐specific expression of IkB α superrepressor due to the inhibition of the NF‐ κ B pathway (Cai et al.…”

Section: Discussionmentioning

confidence: 99%

“…Muscle wasting in these mice was completely blocked by muscle‐specific expression of IkB α superrepressor due to the inhibition of the NF‐ κ B pathway (Cai et al. 2004). Similarly, muscle‐specific expression of dominant‐negative I κ B α diminishes NF‐ κ B activation, decreases levels of ubiquitinated proteins, and inhibits muscle atrophy during unloading (Judge et al.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

et al. 2017

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We tested whether NF‐κB pathway is indispensable for the increase in expression of E3‐ligases and unloading‐induced muscle atrophy using IKKβ inhibitor IMD‐0354. Three groups of rats were used: nontreated control (C), 3 days of unloading/hindlimb suspension with (HS+IMD) or without (HS) IMD‐0354. Levels of IκBα were higher in HS+IMD (1.16‐fold) and lower in HS (0.82‐fold) when compared with C group. IMD‐0354 treatment during unloading: had no effect on loss of muscle mass; increased mRNA levels of MuRF1 and MAFbx; increased level of pFoxO3; and had no effect on levels of Bcl‐3, p105, and p50 proteins. Our study for the first time showed that inhibiting IKK β in vivo during 3‐day unloading failed to diminish expression of ubiquitin ligases and prevent muscle atrophy.

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“…d ‐Trp(8)‐γMSH administration attenuated arthritis‐induced decrease in gastrocnemius mass, cross‐sectional area, mean fast fibre area, and MHC IIa levels. The role of the NF‐ k B transcription factors in the induction of muscle atrophy under conditions of cachexia, associated with increased expression of the E3 ligases MuRF1 and atrogin‐1, is well known 40, 41. Therefore, the anti‐cachectic effect of d ‐Trp(8)‐γMSH treatment can be, in part, secondary to its effect on TNF‐α/NF‐ k B pathway, decreasing ubiquitin‐proteasome activity.…”

Section: Discussionmentioning

confidence: 99%

The melanocortin receptor type 3 agonistd-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats

Gómez-SanMiguel

Martín

Nieto-Bona

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundChronic inflammatory diseases induce cachexia that increases mortality and morbidity of the illness. Adjuvant‐induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. Alpha‐melanocyte stimulating hormone has an anti‐inflammatory effect in arthritic rats and decreases muscle wasting. The aim of this work was to elucidate whether the anti‐cachectic action of alpha‐melanocyte stimulating hormone is mediated by the melanocortin receptor type 3 pathway.MethodsArthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant, and 6 days afterwards, arthritic rats were injected with the selective melanocortin receptor type 3 agonist d‐Trp(8)‐gammaMSH ( d‐Trp(8)‐γMSH) 500 µg/kg subcutaneously. or saline twice a day, for 10 days.Results d‐Trp(8)‐γMSH decreased the external signs of inflammation and body weight loss, but it was not able to modify the anorexigenic effect of arthritis or the increase in hypothalamic cyclooxygenase‐2 (COX‐2) expression. In contrast, d‐Trp(8)‐γMSH prevented arthritis‐induced increase in hypothalamic IL‐1β and serum corticosterone levels and the decrease in serum IGF‐I levels. d‐Trp(8)‐γMSH treatment also prevented arthritis‐induced NF‐kB(p65) phosphorylation and tumour necrosis factor‐α mRNA increase in the gastrocnemius. d‐Trp(8)‐γMSH administration to arthritic rats increased gastrocnemius mass, its cross‐sectional area, and mean fast fibre area. Those effects of d‐Trp(8)‐γMSH were associated with a decreased expression of atrogin‐1 and muscle ring‐finger protein‐1 in the gastrocnemius. In rats treated with saline, arthritis increased the expression of autophagy marker genes LC3b, Bnip‐3, and Gabarap1 as well as the conversion of LC3b I to LC3b II by lipidation in the gastrocnemius. d‐Trp(8)‐γMSH decreased gastrocnemius LC3b, Bnip‐3, and Gabarap1 mRNA expression and prevented the increase in LC3b II in arthritic rats.ConclusionThese data suggest that d‐Trp(8)‐γMSH administration prevents the effect of arthritis on corticosterone and insulin‐like growth factor‐I serum levels and decreases muscle wasting, by down‐regulating atrogenes and autophagy through modifying the NF‐kB(p65)/tumour necrosis factor‐α signalling transduction pathway.

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IKKβ/NF-κB Activation Causes Severe Muscle Wasting in Mice

Cited by 1,203 publications

References 40 publications

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

The melanocortin receptor type 3 agonistd-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats

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