Murine intramyocellular lipids quantified by NMR act as metabolic biomarkers in burn trauma

Tzika, A. Aria; Astrakas, Loukas G.; Cao, Huayang; Mintzopoulos, Dionyssios; Zhang, Qunhao; Padfield, Katie; Yu, Hongue; Mindrinos, Michael; Rahme, Laurence G.; Tompkins, Ronald G.

doi:10.3892/ijmm.21.6.825

Cited by 11 publications

(15 citation statements)

References 42 publications

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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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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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“…We also propose that it is complementary to NMR, which has already shown the consequences of bioenergetic and mitochondrial dysfunction in vivo (22)(23)(24)(25). Thus, our results lead us to conclude that bioenergetic dysfunction and insufficient oxidative defense following local burn trauma may lead to oxidative damage.…”

Section: Discussionmentioning

confidence: 68%

“…In addition to NMR spectroscopy, the development of highthroughput microarray systems, capable of simultaneously measuring the expression of thousands of genes, has also greatly advanced our ability to detect and measure biomarkers. By exploring the expression of certain organ-specific candidate genes, the biological relevance of NMR data can be validated in microarray experiments examining the same specimen (22,23,25). For assessing oxidative damage after burn trauma, in vivo EPR using nitroxides is complementary to NMR since NMR cannot measure redox status and reactive oxygen species (ROS), while EPR can.…”

Section: Introductionmentioning

confidence: 99%

“…NMR is a useful method for measuring biomarkers in vivo, and has already shown relevance in the study of the metabolism and bioenergetics of skeletal muscle (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). In addition to NMR spectroscopy, the development of highthroughput microarray systems, capable of simultaneously measuring the expression of thousands of genes, has also greatly advanced our ability to detect and measure biomarkers.…”

Section: Introductionmentioning

confidence: 99%

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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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“…In vivo studies of 1 H MRS combined with ex vivo HRMAS 1 H MRS have revealed intramyocellular lipids (IMCLs) in rodents (11,17), while other ex vivo HRMAS 1 H MRS studies have focused on lipid metabolism (18). Szczepaniak et al demonstrated that IMCL stores could be quantified accurately in a clinical setting by 1 H NMR spectroscopy in vivo (19).…”

Section: Introductionmentioning

confidence: 99%

In vivo high-resolution magic angle spinning magnetic resonance spectroscopy of Drosophila melanogaster at 14.1 T shows trauma in aging and in innate immune-deficiency is linked to reduced insulin signaling

Tzika¹

2010

Int J Mol Med

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In vivo magnetic resonance spectroscopy (MRS), a non-destructive biochemical tool for investigating live organisms, has yet to be used in the fruit fly Drosophila melanogaster, a useful model organism for investigating genetics and physiology. We developed and implemented a high-resolution magic-angle-spinning (HRMAS) MRS method to investigate live Drosophila at 14.1 T. We demonstrated, for the first time, the feasibility of using HRMAS MRS for molecular characterization of Drosophila with a conventional MR spectrometer equipped with an HRMAS probe. We showed that the metabolic HRMAS MRS profiles of injured, aged wild-type (wt) flies and of immune deficient (imd) flies were more similar to chico flies mutated at the chico gene in the insulin signaling pathway, which is analogous to insulin receptor substrate 1–4 (IRS1–4) in mammals and less to those of adipokinetic hormone receptor (akhr) mutant flies, which have an obese phenotype. We thus provide evidence for the hypothesis that trauma in aging and in innate immune-deficiency is linked to insulin signaling. This link may explain the mitochondrial dysfunction that accompanies insulin resistance and muscle wasting that occurs in trauma, aging and immune system deficiencies, leading to higher susceptibility to infection. Our approach advances the development of novel in vivo non-destructive research approaches in Drosophila, suggests biomarkers for investigation of biomedical paradigms, and thus may contribute to novel therapeutic development.

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Murine intramyocellular lipids quantified by NMR act as metabolic biomarkers in burn trauma

Cited by 11 publications

References 42 publications

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

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

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

In vivo high-resolution magic angle spinning magnetic resonance spectroscopy of Drosophila melanogaster at 14.1 T shows trauma in aging and in innate immune-deficiency is linked to reduced insulin signaling

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