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 γ irradiation totaling 2400 cGy (3 consecutive days × 800 cGy 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.

Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue

“…Peripheral irradiation of mice causes a decrease in voluntary wheel running [20, 33] and, in this study, showed a similar fatigue-like effect in the TFT. This provides further validation that this mouse model induces fatigue and establishes a foundation for future studies to use either or both assays to measure fatigue-like behavior in mice.…”

“…Female C57BL/6 mice were used for chemotherapy-induced fatigue experiments, which used 5-FU to induce fatigue, as this strain and sex was used to establish the TFT [30] and in other studies using 5-FU [19, 31]. Male C57BL/6 mice were used for the radiation-induced fatigue experiment as this strain and sex was used to establish this model [20]. Balb/c mice were used for the colon 26 carcinoma (C26) model as cells used to produce tumors were originally derived from this strain [24].…”

“…In short, male C57BL/6 mice were trained on the treadmill as described previously [30]. On Days 8–10, mice were exposed to 800 cGy of γ irradiation daily (RAD) or underwent a sham procedure, as previously described [20, 33]. On the day before testing, mice received PBS or 1 mg/kg TAL (b.i.d., i.p.).…”

“…Numerous mouse models have been developed and used to recapitulate and better understand CRF produced by various causes, including chemotherapy [17–19], radiation [20], and cancer and cancer cachexia [21–23]. Given the many causes of CRF and the possibility that the underlying mechanisms of CRF may vary depending on the cause, it is important to determine if TAL has anti-fatigue effects in multiple models of CRF.…”

“…The first was a model of chemotherapy-induced fatigue, adapted from a published model [19]. The second was a mouse model of peripheral irradiation that causes fatigue-like behavior by mimicking the peripheral radiation exposure of radiation therapy [20]. The third was a well-established and widely-studied model of cancer cachexia [24–26] in which mice develop tumors that cause fatigue-like behavior [21], muscle wasting, and weight loss [25, 27].…”