Local and Distant Burn Injury Alter Immuno-Inflammatory Gene Expression in Skeletal Muscle

Padfield, Katie; Zhang, Qunhao; Gopalan, Srikanth; Tzika, A. Aria; Mindrinos, Michael; Tompkins, Ronald G.; Rahme, Laurence G.

doi:10.1097/01.ta.0000230567.56797.6c

Cited by 19 publications

(17 citation statements)

References 39 publications

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“…This gene encodes for CCAAT/enhancer binding protein delta (CEBPD), a transcription factor that regulates inflammatory and immune responses . The results coincide with those of studies showing overexpression of this gene in sepsis and burn trauma . In addition, CEBPD binds to the IL6 gene promoter and cooperates with nuclear factor–kappaB (NF‐κB) to stimulate maximal transcription of interleukin‐6, a procachectic cytokine …”

Section: Resultssupporting

confidence: 57%

A differential pattern of gene expression in skeletal muscle of tumor‐bearing rats reveals dysregulation of excitation–contraction coupling together with additional muscle alterations

et al. 2013

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Section: Resultssupporting

confidence: 57%

A differential pattern of gene expression in skeletal muscle of tumor‐bearing rats reveals dysregulation of excitation–contraction coupling together with additional muscle alterations

et al. 2013

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“…The principal findings of the present study are complementary to findings by NMR, suggesting that a major factor in the progression of mitochondrial skeletal muscle dysfunction in burns results from defects in oxidative phosphorylation (OXPHOS) (22)(23)(24)33,34). Indeed, findings with the same mouse 'local' burn model (affecting the hind limb and representing 3-5% of total body surface area) demonstrated that burn injury causes a significant dysregulation in OXPHOS and a decrease in the ATP synthesis rate (23).…”

Section: Discussionsupporting

confidence: 68%

Burn trauma in skeletal muscle results in oxidative stress as assessed by in vivo electron paramagnetic resonance

Tzika¹

2008

Mol Med Rep

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Abstract. Using a mouse model, we tested the hypotheses that severe burn trauma causes metabolic disturbances in skeletal muscle, and that these can be measured and repeatedly followed by in vivo electron paramagnetic resonance (EPR). We used a 1.2-GHz (L-band) EPR spectrometer to measure partial pressure of oxygen (pO 2 ) levels, redox status and oxidative stress following a non-lethal burn trauma model to the left hind limbs of mice. Results obtained in the burned mouse gastrocnemius muscle indicated a significant decrease in tissue pO 2 immediately (P=0.032) and at 6 h post burn (P=0.004), compared to the gastrocnemius of the unburned hind limb. The redox status of the skeletal muscle also peaked at 6 h post burn (P=0.027) in burned mice. In addition, there was an increase in the EPR signal of the nitroxide produced by oxidation of the hydroxylamine (CP-H) probe at 12 h post burn injury, indicating a burn-induced increase in mitochondrial reactive oxygen species (ROS). The nitroxide signal continued to increase between 12 and 24 h, suggesting a further increase in ROS generation post burn. These results confirm genomic results, which indicate a downregulation of antioxidant genes and therefore strongly suggest the dysfunction of the mitochondrial oxidative system. We believe that the direct measurement of tissue parameters such as pO 2 , redox and ROS by EPR may be used to complement measurements by nuclear magnetic resonance (NMR) in order to assess tissue damage and the therapeutic effectiveness of antioxidant agents in severe burn trauma.

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“…Meanwhile, decreased expression of PGC-1ß appears to: a) upregulate UCP3, leading to uncoupling and reduced ATP synthesis rate; and b) alter immuno-inflammatory gene expression in skeletal muscle [in cachexia Fig. 1; in experimental burn injury (31,33,34,36)]. This supposition is in agreement with other studies suggesting that upregulation of mRNA and protein expression of UCP2 and UCP3 (12–14) correlates directly with antioxidative capacity (15,16) in response to elevated TNFα-induced ROS production in cancer (60).…”

Section: Discussionmentioning

confidence: 99%

Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia

Argilï¿1⁄2s¹

2010

Int J Mol Med

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Cancer patients commonly suffer from cachexia, a syndrome in which tumors induce metabolic changes in the host that lead to massive loss in skeletal muscle mass. Using a preclinical mouse model of cancer cachexia, we tested the hypothesis that tumor inoculation causes a reduction in ATP synthesis and genome-wide aberrant expression in skeletal muscle. Mice implanted with Lewis lung carcinomas were examined by in vivo 31P nuclear magnetic resonance (NMR). We examined ATP synthesis rate and the expression of genes that play key-regulatory roles in skeletal muscle metabolism. Our in vivo NMR results showed reduced ATP synthesis rate in tumor-bearing (TB) mice relative to control (C) mice, and were cross-validated with whole genome transcriptome data showing atypical expression levels of skeletal muscle regulatory genes such as peroxisomal proliferator activator receptor γ coactivator 1 ß (PGC-1ß), a major regulator of mitochondrial biogenesis and, mitochondrial uncoupling protein 3 (UCP3). Aberrant pattern of gene expression was also associated with genes involved in inflammation and immune response, protein and lipid catabolism, mitochondrial biogenesis and uncoupling, and inadequate oxidative stress defenses, and these effects led to cachexia. Our findings suggest that reduced ATP synthesis is linked to mitochondrial dysfunction, ultimately leading to skeletal muscle wasting and thus advance our understanding of skeletal muscle dysfunction suffered by cancer patients. This study represents a new line of research that can support the development of novel therapeutics in the molecular medicine of skeletal muscle wasting. Such therapeutics would have wide-spread applications not only for cancer patients, but also for many individuals suffering from other chronic or endstage diseases that exhibit muscle wasting, a condition for which only marginally effective treatments are currently available.

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Local and Distant Burn Injury Alter Immuno-Inflammatory Gene Expression in Skeletal Muscle

Abstract: Burn mediates a common systemic response, independent of the site or extent of injury, and also specific responses to local versus distant trauma. A transcriptome profile of genes that initiate and sustain systemic inflammation has been identified.

Cited by 19 publications

References 39 publications

A differential pattern of gene expression in skeletal muscle of tumor‐bearing rats reveals dysregulation of excitation–contraction coupling together with additional muscle alterations

A differential pattern of gene expression in skeletal muscle of tumor‐bearing rats reveals dysregulation of excitation–contraction coupling together with additional muscle alterations

Burn trauma in skeletal muscle results in oxidative stress as assessed by in vivo electron paramagnetic resonance

Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia

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