Exercise Improves Cancer-free Survival and Health Span in a Model of Radiation-induced Cancer

Abstract

Introduction: Radiation therapy increases the risk of secondary malignancy and morbidity in cancer survivors. The role of obesity and exercise training in modulating this risk is not well understood. As such, we used a preclinical model of radiation-induced malignancy to investigate whether diet-induced obesity and/or endurance exercise training altered lifelong survival, cancer incidence, and morbidity. Methods: Male CBA mice were randomly divided into control diet/sedentary group (CTRL/SED), high-fat diet (45% fat)/sedentary group (HFD/SED), control diet/exercise group (2-3 d•wk −1 ; CTRL/EX), or high-fat diet/exercise group (HFD/EX) groups then exposed to whole-body radiation (3 Gy). End point monitoring and pathology determined mortality and cancer incidence, respectively. Health span index, a measure of morbidity, was determined by a composite measure of 10 anthropometric, metabolic, performance, and behavioral measures. Results: Overall survival was higher in HFD/SED compared with CTRL/SED (P < 0.05). The risk of cancer-related mortality by 18 months postradiation was 1.99 and 1.63 in HFD/SED compared with CTRL/EX (RR = 1.99, 95% confidence interval = 1.20-3.31, P = 0.0081) and CTRL/SED (RR = 1.63, 95% confidence interval = 1.06-2.49, P = 0.0250), respectively. The number of mice at end point with cancer was higher in HFD/SED compared with CTRL/EX and CTRL/SED (P < 0.05). Health span index was highest in CTRL/EX (score = +2.5), followed by HFD/EX (score = +1), and HFD/SED (score = −1) relative to CTRL/SED. Conclusion: This work provides the basis for future preclinical studies investigating the dose-response relationship between exercise training and late effects of radiation therapy as well as the mechanisms responsible for these effects.

Resistance and endurance exercise training improves muscle mass and the inflammatory/fibrotic transcriptome in a rhabdomyosarcoma model

“…Body composition and body weight were assessed by EchoMRI‐900 (EchoMRI LLC) and an electronic scale as previously described 18,19 . Endurance performance was evaluated on a motorized treadmill as previously described without electric shock 19 .…”

The role of exercise-and high fat diet-induced bone marrow extracellular vesicles in stress hematopoiesis

“…Correlational findings from clinical studies suggest lower miR-331-5p expression is related to leukemia relapse (Feng et al, 2011) and worsened responses to therapies for acute myeloid leukemia (Butrym et al, 2015). Previous data from our lab has shown that acute myeloid leukemia incidence is increased with HFD, that is, attenuated by exercise throughout the lifespan (Farber et al, 2021), thus downregulated miR-331-5p expression in HFD-EX EVs may be implicated in this observation. Relatively more information is available regarding miR-193 and hematopoiesis.…”

“…Mice in Cohort 1 underwent an endurance test using a Exer 3/6 treadmill (Columbus Instruments, Columbus, OH, United States) angled upwards at 5°, as described previously, to evaluate training status ( Baker et al, 2011 ; De Lisio et al, 2011 , 2013 ; De Lisio and Parise, 2012 ; Emmons et al, 2019 ; Farber et al, 2021 ). All mice were acclimated for 10 min at 8 m min −1 the week prior to the endurance test.…”

“…The mice were encouraged to run using a soft-bristle paint brush; electric shock was not used for any test. Following the endurance test, Cohort 1 mice underwent an exercise training program, as described previously ( Baker et al, 2011 ; Emmons et al, 2019 ; Farber et al, 2021 ). The exercise training program involved three exercise sessions per week for 40–60 min, depending on the training week.…”

How Does Lifestyle Affect Hematopoiesis and the Bone Marrow Microenvironment?

“… 9 , 83 Importantly, this increased hematopoietic activity in exercise-trained mice in the context of stress hematopoiesis does not appear to result in increased risk of hematological malignancies; however, the risk of hematological malignancies is increased in experimental models of obesity. 84 With respect to HSC fate decisions, exercise training induces a notable decrease in HSC myeloid-skewing under obesogenic conditions 4 and an increase in lymphopoiesis. 83 Collectively, these results suggest that, regardless of the effects of exercise training on HSC content, exercise training improves the functional capacity of HSCs to respond to hematopoietic stress and may restore HSC lineage commitment to reverse the inflammatory phenotype in obesity.…”