Inflammation plays a causal role in fatigue-like behavior induced by pelvic irradiation in mice.

Fatigue is a persistent and debilitating symptom following radiation therapy for prostate cancer. However, it is not well-understood how radiation targeted to a small region of the body can lead to broad changes in behavior. In this study, we used targeted pelvic irradiation of healthy male mice to test whether inflammatory signaling mediates changes in voluntary physical activity levels. First, we tested the relationship between radiation dose, blood cell counts, and fatigue-like behavior measured as voluntary wheel-running activity. Next, we used oral minocycline treatments to reduce inflammation and found that minocycline reduces, but does not eliminate, the fatigue-like behavioral changes induced by radiation. We also used a strain of mice lacking the MyD88 adaptor protein and found that these mice also showed less fatigue-like behavior than the wild-type controls. Finally, using serum and brain tissue samples, we determined changes in inflammatory signaling induced by irradiation in wild-type, minocycline treated, and MyD88 knockout mice. We found that irradiation increased serum levels of IL-6, a change that was partially reversed in mice treated with minocycline or lacking MyD88. Overall, our results suggest that inflammation plays a causal role in radiation-induced fatigue and that IL-6 may be an important mediator.

Extracellular matrix influences astrocytic extracellular vesicle function in wound repair.

Astrocytic injury responses are known to be influenced by the extracellular matrix (ECM). Astrocytes are also recognized as a source of extracellular vesicles (EVs) that can impact the activity and function of other astrocytes and cell types. Whether the ECM influences the function of astrocytic EVs in the context of wound recovery has not been previously studied. We report EVs from astrocytes cultured on varied ECM substrates are sufficient to elicit distinct injury responses in naive astrocytes that recapitulate the effects of the ECM of origin. When compared with wound recovery on control substrates, EVs from ECM-exposed astrocytes elicited accelerated rates of wound recovery that varied based on each ECM. When EVs were collected from IL-1ß treated and ECM-exposed astrocyte cultures, we found that IL-1ß arrested wound recovery in naive astrocytes treated with EVs from astrocytes cultured on ECM but adding EVs from IL-1ß treated Tenascin-c-cultured astrocytes increased wound recovery. To confirm that ECM was a primary influence on these astrocytic EV functions, we tested the contribution of ß1-integrin, a major integrin receptor for the ECM molecules tested in this study. We found that the ß1-integrin inhibitor Ha2/5, resulted in EVs that significantly attenuated the wound recovery of naive astrocytes. This provides new information on the importance of culture substrates on astrocytic responses, EV functions and injury responses that may impact the understanding of astroglial responses related to ECM compositional differences in diverse physiological states.

Brain-derived neurotrophic factor polymorphism Val66Met protects against cancer-related fatigue.

Cancer-related fatigue is an extremely common and debilitating psychiatric symptom that affects up to 80% of cancer patients. Despite its negative impact on the patient's quality of life, there is no well-established biomarker or mechanisms associated with this debilitating condition. The functional brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with a variety of psychiatric illnesses. We hypothesized that Val66Met may influence the risk for developing cancer-related fatigue. BDNF Val66Met was analyzed by polymerase chain reaction in 180 patients with confirmed cancer diagnoses. Fatigue was measured using the Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) questionnaire. Depression was measured using the Hamilton Depression Scale (HAM-D). Data were transformed when necessary and regression models were constructed to access the association between genotype and symptom severity. Participants carrying the Met allele reported significantly less fatigue compared to the Val/Val genotype group. The presence of the Met allele did not influence depression levels. The results suggest that the BDNF Val66Met polymorphism confers protective advantage against cancer-related fatigue; whereas having the Val/Val genotype may be a genetic risk factor. Findings from this study not only provide clues to the neural basis of cancer-related fatigue, but also allow for symptom severity prediction and patient education with the goal to improve symptom management.

Induction of fatigue-like behavior by pelvic irradiation of male mice alters cognitive behaviors and BDNF expression.

Fatigue and cognitive deficits are often co-occurring symptoms reported by patients after radiation therapy for prostate cancer. In this study, we induced fatigue-like behavior in mice using targeted pelvic irradiation to mimic the clinical treatment regimen and assess cognitive behavioral changes. We observed that pelvic irradiation produced a robust fatigue phenotype, a reduced rate of spontaneous alternation in a Y-maze test, and no behavioral change in an open field test. We found that reversal learning for fatigued mice was slower with respect to time, but not with respect to effort put into the test, suggesting that fatigue may impact the ability or motivation to work at a cognitive task without impairing cognitive capabilities. In addition, we found that mice undergoing pelvic irradiation show lower whole-brain levels of mature BDNF, and that whole-brain proBDNF levels also correlate with spontaneous alternation in a Y-maze test. These results suggest that changes in BDNF levels could be both a cause and an effect of fatigue-related changes in behavior.

Measuring the Motor Aspect of Cancer-Related Fatigue using a Handheld Dynamometer.

Cancer-related fatigue (CRF) is commonly reported by patients both during and after receiving treatment for cancer. Current CRF diagnoses rely on self-report questionnaires which are subject to report and recall biases. Objective measurements using a handheld dynamometer, or handgrip device, have been shown in recent studies to correlate significantly with subjective self-reported fatigue scores. However, variations of both the handgrip fatigue test and fatigue index calculations exist in the literature. The lack of standardized methods limits the utilization of the handgrip fatigue test in the clinical and research settings. In this study, we provide detailed methods for administering the physical fatigue test and calculating the fatigue index. These methods should supplement existing self-reported fatigue questionnaires and help clinicians assess fatigue symptom severity in an objective and quantitative manner.

[Corrigendum] Cancer­related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction.

Following the publication of the article, the authors realized that they have overlooked acknowledging the assistance they received from the Murine Phenotyping Core at NHLBI. Therefore, the Acknowledgements section of the Declarations should also have stated the following: 'We would like to thank the Murine Phenotyping Core at NHLBI for all their help with the mouse experiments, including Dr Danielle Springer, Audrey Noguchi, Michele Allen, Heather Potts and Morteza Peiravi.' The authors regret their oversight in failing to include this information in the Acknowledgements section of their paper. [the original article was published in International Journal of Molecular Medicine 45: 485­496, 2020; DOI: 10.3892/ijmm.2019.4435].

Cancer­related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction.

Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non­metastatic prostate cancer (NMPC). Despite the efficacy, treatment­related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. A total of 64 participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy­Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants' whole blood. An ADT/RT­induced fatigue mouse model was developed, with fatigue measured as a reduction in voluntary wheel­running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using western blot analysis of glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). The results demonstrated that fatigue in the ADT group was exacerbated during RT compared with the non­ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non­fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated the synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. In conclusion, these findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model and its mechanism may be related to bioenergetics in the CNS.