Creatine–Creatinine Metabolism in Radiation Myopathy

Haberland, G. L.; Schreier, K; Bruns, Friedrich; Altman, Kurt I.; Hempelmann, Louis H.

doi:10.1038/1751039a0

Cited by 26 publications

(7 citation statements)

References 4 publications

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“…Creatine can be synthesized in the liver or kidney through arginine amidino group transfer to glycine by enzymatic action of glycine amidinotransferase forming guanidinoacetate and subsequent methylation by guanidinoacetate Nmethyltransferase. Changes in creatine and resulting muscular weakness have long been observed from radiation exposure (27). Creatine increased in serum at 24 h and returned to basal levels at 36-96 h, which is consistent with patterns observed in urine (28), however, it increased again at day 7 after >.7 Gy doses (26).…”

Section: Lc-ms Global Metabolomicssupporting

confidence: 80%

Nonhuman Primates with Acute Radiation Syndrome: Results from a Global Serum Metabolomics Study after 7.2 Gy Total-Body Irradiation

Pannkuk¹,

Laiakis²,

Garcia³

et al. 2018

Radiation Research

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Threats of nuclear terrorism coupled with potential unintentional ionizing radiation exposures have necessitated the need for large-scale response efforts of such events, including high-throughput biodosimetry for medical triage. Global metabolomics utilizing mass spectrometry (MS) platforms has proven an ideal tool for generating large compound databases with relative quantification and structural information in a short amount of time. Determining metabolite panels for biodosimetry requires experimentation to evaluate the many factors associated with compound concentrations in biofluids after radiation exposures, including temporal changes, pre-existing conditions, dietary intake, partial- vs. total-body irradiation (TBI), among others. Here, we utilize a nonhuman primate (NHP) model and identify metabolites perturbed in serum after 7.2 Gy TBI without supportive care [LD, hematologic (hematopoietic) acute radiation syndrome (HARS) level H3] at 24, 36, 48 and 96 h compared to preirradiation samples with an ultra-performance liquid chromatography quadrupole time-of-flight (UPLC-QTOF) MS platform. Additionally, we document changes in cytokine levels. Temporal changes observed in serum carnitine, acylcarnitines, amino acids, lipids, deaminated purines and increases in pro-inflammatory cytokines indicate clear metabolic dysfunction after radiation exposure. Multivariate data analysis shows distinct separation from preirradiation groups and receiver operator characteristic curve analysis indicates high specificity and sensitivity based on area under the curve at all time points after 7.2 Gy irradiation. Finally, a comparison to a 6.5 Gy (LD, HARS level H2) cohort after 24 h postirradiation revealed distinctly increased separations from the 7.2 Gy cohort based on multivariate data models and higher compound fold changes. These results highlight the utility of MS platforms to differentiate time and absorbed dose after a potential radiation exposure that may aid in assigning specific medical interventions and contribute as additional biodosimetry tools.

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Section: Lc-ms Global Metabolomicssupporting

confidence: 80%

Nonhuman Primates with Acute Radiation Syndrome: Results from a Global Serum Metabolomics Study after 7.2 Gy Total-Body Irradiation

Pannkuk¹,

Laiakis²,

Garcia³

et al. 2018

Radiation Research

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“…However, previous experiments carried out in this laboratory on in vivo synthesis of creatine from glycine-1-C14 in rats exposed to xirradiation ( 2 ) do not support the hypothesis of an increased creatine synthesis. To determine whether creatine synthesis is increased after exposure to radiation, the rate of creatine synthesis from glycocyamine-2-CI4 in the isolated perfused liver of normal and x-irradiated rats has been studied and is reported here.…”

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confidence: 55%

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mentioning

confidence: 99%

Greatine Synthesis in the Perfused Liver of Normal and X-irradiated Rats

Gerber

Koszalka

Miller

1962

Experimental Biology and Medicine

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One of the metabolic disorders observed in animals after exposure to ionizing radiation is an intense creatinuria ( 1,2,3,4). Recent studies indicate that the depressed capacity of the skeletal muscle to utilize creatine is responsible for the creatinuria observed after irradiation(5,6). On the basis of in vitro studies with liver homogenates it has also been suggested that the synthesis of creatine from glycocyamine is increased after x-irradiation ( 7).However, previous experiments carried out in this laboratory on in vivo synthesis of creatine from glycine-1-C14 in rats exposed to xirradiation( 2 ) do not support the hypothesis of an increased creatine synthesis. To determine whether creatine synthesis is increased after exposure to radiation, the rate of creatine synthesis from glycocyamine-2-CI4 in the isolated perfused liver of normal and x-irradiated rats has been studied and is reported here.Methods. Four rats of Sprague-Dawley strain were exposed to 650 r of x-rays(4) and starved thereafter for 18 hours. At this time, a significant elevation of the creatine levels of blood and urine was observed. Four other rats of the same strain, also starved for 18 hours, served as controls.The liver was removed from each rat and perfused with whole heparinized blood diluted with one-third volume of Ringer's solution containing 250 mg of glucose and 4 pc of glycocyamine-2-CI4 (0.185 mg) (purchased from the California Biochemical Corp.) . Blood donors were non-irradiated adult Sprague-Dawley rats fasted 18 to 20 hours before bleeding. Details of the perfusion technic and apparatus have been previously described ( 8,9).

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“…It is essential to healthy cell and tissue function and is utilized by the amino acid pathway [86]. Elevated levels of creatine in urine are likely due to the inability of injured muscle to take up and use the available metabolite [18,42,45,87]. IR induced myopathy has been observed in human and animal studies, however the causative mechanism has yet to be elucidated [87][88][89].…”

Section: Creatinementioning

confidence: 99%

A Systematic Review of Metabolomic and Lipidomic Candidates for Biomarkers in Radiation Injury

2020

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A large-scale nuclear event has the ability to inflict mass casualties requiring point-of-care and laboratory-based diagnostic and prognostic biomarkers to inform victim triage and appropriate medical intervention. Extensive progress has been made to develop post-exposure point-of-care biodosimetry assays and to identify biomarkers that may be used in early phase testing to predict the course of the disease. Screening for biomarkers has recently extended to identify specific metabolomic and lipidomic responses to radiation using animal models. The objective of this review was to determine which metabolites or lipids most frequently experienced perturbations post-ionizing irradiation (IR) in preclinical studies using animal models of acute radiation sickness (ARS) and delayed effects of acute radiation exposure (DEARE). Upon review of approximately 65 manuscripts published in the peer-reviewed literature, the most frequently referenced metabolites showing clear changes in IR induced injury were found to be citrulline, citric acid, creatine, taurine, carnitine, xanthine, creatinine, hypoxanthine, uric acid, and threonine. Each metabolite was evaluated by specific study parameters to determine whether trends were in agreement across several studies. A select few show agreement across variable animal models, IR doses and timepoints, indicating that they may be ubiquitous and appropriate for use in diagnostic or prognostic biomarker panels.

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Creatine–Creatinine Metabolism in Radiation Myopathy

Cited by 26 publications

References 4 publications

Nonhuman Primates with Acute Radiation Syndrome: Results from a Global Serum Metabolomics Study after 7.2 Gy Total-Body Irradiation

Nonhuman Primates with Acute Radiation Syndrome: Results from a Global Serum Metabolomics Study after 7.2 Gy Total-Body Irradiation

Greatine Synthesis in the Perfused Liver of Normal and X-irradiated Rats

A Systematic Review of Metabolomic and Lipidomic Candidates for Biomarkers in Radiation Injury

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