Dataset Information

A murine model of peripheral irradiation-induced fatigue.

ABSTRACT: PURPOSE:Fatigue is the most ubiquitous side effect of cancer treatment, but its etiology remains elusive. Further investigations into cancer-related fatigue pathobiology necessitate the expanded use of animal models. This study describes the development of a murine model of radiation-induced fatigue. METHODS:Voluntary wheel running activity measured fatigue in 5-8 week-old, male C57BL/6 mice before and after ? irradiation totaling 2400cGy (3 consecutive days×800cGy daily fractionated doses) to the lower abdominal areas. Three trials confirmed fatigue behavior at this dose. Anhedonia, body weight, and hemoglobin were also measured. Gastrointestinal, skeletal muscle, and bone marrow tissue samples were evaluated for signs of damage. RESULTS:In two validation trials, irradiated mice (trial 1, n=8; trial 2, n=8) covered less cumulative distance in kilometers post-irradiation (trial 1, mean=115.3±12.3; trial 2, mean=113.6±21.8) than sham controls (trial 1, n=5, mean=126.3±5.7, p=0.05; trial 2, n=8, mean=140.9±25.4, p=0.02). Decreased mean daily running distance and speed were observed during the last four hours of the dark cycle in irradiated mice compared to controls for two weeks post-irradiation. There were no differences in saccharin preference or hemoglobin levels between groups, no effect of changes in body weight or hemoglobin on wheel running distance, additionally, histology showed no damage to muscle, bone marrow, or gastrointestinal integrity, with the latter confirmed by ELISA. CONCLUSION:We characterized a novel mouse model of fatigue caused by peripheral radiation and not associated with anemia, weight changes, or anhedonia. This model provides opportunities for detailed study of the mechanisms of radiation-induced fatigue.

SUBMITTER: Renner M

PROVIDER: S-EPMC4853268 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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A murine model of peripheral irradiation-induced fatigue.

Renner Michael M Feng Rebekah R Springer Danielle D Chen Mei-Kuang MK Ntamack Andre A Espina Alexandra A Saligan Leorey N LN

Behavioural brain research 20160321

<h4>Purpose</h4>Fatigue is the most ubiquitous side effect of cancer treatment, but its etiology remains elusive. Further investigations into cancer-related fatigue pathobiology necessitate the expanded use of animal models. This study describes the development of a murine model of radiation-induced fatigue.<h4>Methods</h4>Voluntary wheel running activity measured fatigue in 5-8 week-old, male C57BL/6 mice before and after γ irradiation totaling 2400cGy (3 consecutive days×800cGy daily fractiona ...[more]

PMID: 27012391

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Project description:The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-?)-induced persistent fatigue as a model of CFS. IFN-?, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-? treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-? treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-? treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-?, compared with patients who did not (? Treatment Week (TW)-0 vs. TW4; PF: 7.1?±?1.5 vs. RF: 4.0?±?0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-? treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p?=? 0.011 for IL-6 and p?=?0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-?, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Project description:Background:Clinical tests for detecting central and peripheral shoulder fatigue are limited. The discrimination of these two types of fatigue is necessary to better adapt recovery intervention. The Kinematic Theory of Rapid Human Movements describes the neuromotor impulse response using lognormal functions and has many applications in pathology detection. The ideal motor control is modeled and a change in the neuromuscular system is reflected in parameters extracted according to this theory. Objective:The objective of this study was to assess whether a shoulder neuromuscular fatigue could be detected through parameters describing the theory, if there is the possibility to discriminate central from peripheral fatigue, and which handwriting test gives the most relevant information on fatigue. Methods:Twenty healthy participants performed two sessions of fast stroke handwriting on a tablet, before and after a shoulder fatigue. The fatigue was in internal rotation for one session and in external rotation during the other session. The drawings consisted of simple strokes, triangles, horizontal, and vertical oscillations. Parameters of these strokes were extracted according to the Sigma-Lognormal model of the Kinematic Theory. The evolution of each participant was analyzed through a U-Mann-Whitney test for individual comparisons. A Hotelling's T 2-test and a U-Mann-Whitney test were also performed on all participants to assess the group evolution after fatigue. Moreover, a correlation among parameters was calculated through Spearman coefficients to assess intrinsic parameters properties of each handwriting test. Results:Central and peripheral parameters were statistically different before and after fatigue with a possibility to discriminate them. Participants had various responses to fatigue. However, when considering the group, parameters related to the motor program execution showed significant increase in the handwriting tests after shoulder fatigue. The test of simple strokes permits to know more specifically where the fatigue comes from, whereas the oscillations tests were the most sensitive to fatigue. Conclusion:The results of this study suggest that the Sigma-Lognormal model of the Kinematic Theory is an innovative approach for fatigue detection with discrimination between the central and peripheral systems. Overall, there is a possibility to implement the setting for clinics and sports personalized follow-up.

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A murine model of peripheral irradiation-induced fatigue.

Publications

A murine model of peripheral irradiation-induced fatigue.

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