Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury

Yarar‐Fisher, Ceren; Bickel, C. Scott; Kelly, Nicholas M.; Stec, Michael J.; Windham, Samuel T.; McLain, Amie; Oster, Robert A.; Bamman, Marcas M.

doi:10.1152/ajpendo.00240.2015

Cited by 31 publications

(39 citation statements)

References 45 publications

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“…Data are presented as means ± 95% confidence intervals were no changes in the mRNA expression of IL-6, TNFα, or TWEAK. These elevations were seen together with greater Fn14 and activated NF-κB-p65 protein expression and further suggest greater inflammation sensitivity in paralyzed muscle (Yarar-Fisher, Bickel, & Kelly, 2016). Our current data conflicts with our previous study in mice in which we reported an upregulation of pro-inflammatory cytokines in the gastrocnemius of paralyzed mice following a complete spinal cord transection (Graham et al, 2015).…”

Section: Discussioncontrasting

confidence: 99%

Contusion spinal cord injury upregulates p53 protein expression in rat soleus muscle at multiple timepoints but not key senescence cytokines

et al. 2020

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To determine whether muscle disuse after a spinal cord injury (SCI) produces elevated markers of cellular senescence and induces markers of the senescence‐associated secretory phenotypes (SASPs) in paralyzed skeletal muscle. Four‐month‐old male Sprague‐Dawley rats received a moderate‐severe (250 kiloDyne) T‐9 contusion SCI or Sham surgery and were monitored over 2 weeks, and 1‐, 2‐, or 3 months. Animals were sacrificed via isoflurane overdose and terminal exsanguination and the soleus was carefully excised and snap frozen. Protein expression of senescence markers p53, p27, and p16 was determined from whole soleus lysates using Western immunoblotting and RT‐qPCR was used to determine the soleus gene expression of IL‐1α, IL‐1β, IL‐6, CXCL1, and TNFα. SCI soleus muscle displayed 2‐ to 3‐fold higher total p53 protein expression at 2 weeks, and at 1 and 2 months when compared with Sham. p27 expression was stable across all groups and timepoints. p16 protein expression was lower at 3 months in SCI versus Sham, but not earlier timepoints. Gene expression was relatively stable between groups at 2 weeks. There were Surgery x Time interaction effects for IL‐6 and TNFα mRNA expression but not for IL‐1α, IL‐1β, or CXCL1. There were no main effects for time or surgery for IL‐1α, IL‐1β, or CXCL1, but targeted t tests showed reductions in IL‐1α and CXCL1 in SCI animals compared to Sham at 3 months and IL‐1β was reduced in SCI animals compared to Sham animals at the 2‐month timepoint. The elevation in p53 does not appear consistent with the induction of SASP because mRNA expression of cytokines associated with senescence was not uniformly upregulated and, in some instances, was downregulated in the early chronic phase of SCI.

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Section: Discussioncontrasting

confidence: 99%

Contusion spinal cord injury upregulates p53 protein expression in rat soleus muscle at multiple timepoints but not key senescence cytokines

et al. 2020

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“…It is also an important transcription factor, which has a proinflammatory role in the inflammatory response and possesses a variety of biological functions (21,22). SCI activates NF-κB in glial, neural and vascular endothelial cells, causing the activation of NF-κB.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of geraniol inhibits inflammatory response, oxidative stress and apoptosis in traumatic injury of the spinal cord through modulation of NF-κB and p38 MAPK

Wang

Zhu

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Geraniol is a type of monoterpenoid with a rose scent and a slightly sweet flavor. It is found in the volatile oil of various plants, and has anti-inflammatory and anti-oxidant effects. The present study aimed to investigate the protective effect of geraniol in inhibiting the inflammatory response, oxidative stress and apoptosis in traumatic spinal cord injury (SCI), as well as to analyze the mechanism underlying its effect. Adult male Sprague-Dawley rats were induced to traumatic SCI through a surgical procedure and were defined as the SCI model group. SCI or normal rats were then administered 250 mg/kg/day geraniol for 4 weeks. The Basso, Beattie and Bresnahan (BBB) test and the spinal cord water content were used to analyze the effect of geraniol against traumatic SCI in rats. The inflammatory response, oxidative stress, and caspase-9 and -3 activities were measured using commercial ELISA kits. In addition, the associated mechanism was analyzed, using western blot analysis to determine the protein expression levels of nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK). The results of the present study demonstrated that BBB scores were significantly increased and the spinal cord water content was significantly inhibited in SCI rats after 3 weeks of geraniol treatment. Furthermore, the inflammatory response, oxidative stress, and the caspase-9 and -3 activities were significantly suppressed upon treatment with geraniol. Finally, the mechanism of geraniol against traumatic SCI downregulated the NF-κB and p38 MAPK pathways in SCI rats. Therefore, the protective effect of geraniol is suggested to inhibit the inflammatory response, oxidative stress and apoptosis in traumatic SCI through the modulation of NF-κB and p38 MAPK.

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“…A marked increase in vastus lateralis mRNA expression of TNFα-, TNF-like weak inducer of apoptosis (TWEAK)-and interleukin (IL)-6-family cytokines and receptors 5-days post burn injury suggests changes in inflammatory signaling may contribute to the observed atrophy (Merritt et al, 2013b). Similarly, elevated expression of TWEAK and TNFα receptors has been observed in paralyzed muscle of men with chronic spinal cord injury, a condition that also presents with muscle atrophy and impaired regenerative capacity (Yarar-Fisher et al, 2016). The opposing regulatory roles of local inflammatory signaling in myogenesis and muscle mass maintenance indicate the post-injury or post-operative inflammatory response must be well-controlled to maintain muscle mass and allow for adequate tissue regeneration.…”

Section: Potential Consequences Of Heightened Intramuscular Inflammatmentioning

confidence: 99%

Divergent Roles of Inflammation in Skeletal Muscle Recovery From Injury

et al. 2020

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A transient increase in local pro-inflammatory cytokine expression following skeletal muscle injury mediates the repair and regeneration of damaged myofibers through myogenesis. Regenerative capacity is diminished and muscle wasting occurs, however, when intramuscular inflammatory signaling is exceedingly high or persists chronically. An excessive and persistent inflammatory response to muscle injury may therefore impair recovery by limiting the repair of damaged tissue and triggering muscle atrophy. The concentration-dependent activation of different downstream signaling pathways by several pro-inflammatory cytokines in cell and animal models support these opposing roles of post-injury inflammation. Understanding these molecular pathways is essential in developing therapeutic strategies to attenuate excessive inflammation and accelerate functional recovery and muscle mass accretion following muscle damage. This is especially relevant given the observation that basal levels of intramuscular inflammation and the inflammatory response to muscle damage are not uniform across all populations, suggesting certain individuals may be more susceptible to an excessive inflammatory response to injury that limits recovery. This narrative review explores the opposing roles of intramuscular inflammation in muscle regeneration and muscle protein turnover. Factors contributing to an exceedingly high inflammatory response to damage and age-related impairments in regenerative capacity are also considered.

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Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury

Abstract: McLain AB, Oster RA, Bamman MM. Heightened TWEAK-NF-B signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury.

Cited by 31 publications

References 45 publications

Contusion spinal cord injury upregulates p53 protein expression in rat soleus muscle at multiple timepoints but not key senescence cytokines

Contusion spinal cord injury upregulates p53 protein expression in rat soleus muscle at multiple timepoints but not key senescence cytokines

Protective effect of geraniol inhibits inflammatory response, oxidative stress and apoptosis in traumatic injury of the spinal cord through modulation of NF-κB and p38 MAPK

Divergent Roles of Inflammation in Skeletal Muscle Recovery From Injury

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