The Late Effects of Radiation Therapy on Skeletal Muscle Morphology and Progenitor Cell Content are Influenced by Diet-Induced Obesity and Exercise Training in Male Mice

Abstract

Radiation exposure during muscle development induces long-term decrements to skeletal muscle health, which contribute to reduced quality of life in childhood cancer survivors. Whether the effects of radiation on skeletal muscle are influenced by relevant physiological factors, such as obesity and exercise training remains unknown. Using skeletal muscle from our previously published work examining the effects of obesity and exercise training on radiation-exposed bone marrow, we evaluated the influence of these physiological host factors on irradiated skeletal muscle morphology and cellular dynamics. Mice were divided into control and high fat diet groups with or without exercise training. All mice were then exposed to radiation and continued in their intervention group for an additional 4 weeks. Diet-induced obesity resulted in increased muscle fibrosis, while obesity and exercise training both increased muscle adiposity. Exercise training enhanced myofibre cross-sectional area and the number of satellite cells committed to the myogenic lineage. High fat groups demonstrated an increase in p-NFĸB expression, a trend for a decline in IL-6 , and increase in TGFB1 . These findings suggest exercise training improves muscle morphology and satellite cell dynamics compared to diet-induced obesity in irradiated muscle, and have implications for exercise interventions in cancer survivors.

Role of Metabolic Stress and Exercise in Regulating Fibro/Adipogenic Progenitors

“…However, we were not able to distinguish between intermuscular and intramyocellular adipose tissue in our analyses. Conversely, FAP content trended to increase in high fat-fed, sedentary mice, and trended to be reduced in high fat-fed, exercise trained mice (D'Souza et al, 2019). While these results are preliminary, they suggest that exercise training may inhibit FAP expansion in obesity.…”

“…Furthermore, acute resistance and endurance exercise is known to increase muscle extracellular matrix synthesis with a similar increase in breakdown resulting in matrix remodeling without excessive accumulation, unlike pathological conditions (Martinez-Huenchullan et al, 2017). Using a preclinical model of radiation exposure, recent work from our group showed a differential FAP response of obese and exercise trained mice (D'Souza et al, 2019). Interestingly muscle fibrosis and adipose tissue accumulation were higher in high fat-fed mice with no effect of treadmill exercise.…”

“…Similarly, recent work from our laboratory using a model of in vivo radiation exposure demonstrated that high fat feeding increased levels of phosphorylated NF-κB, particularly in interstitial nuclei (D'Souza et al, 2019). However, it was not evident if this marker of increased interstitial NF-κB activation was localized specifically to FAPs (D'Souza et al, 2019). In the context of aging, Lukjanenko et al (2019) determined that diminished FAP secretion of the matricellular protein WNT1 inducible signaling pathway protein 1 (WISP-1) underlies the impairment in MuSC regenerative capacity.…”

Mechanisms of Energy Metabolism in Skeletal Muscle Mitochondria Following Radiation Exposure

“…Fortunately, improvements in the ability to detect and treat cancer have resulted in a 60% survival rate of five years after cancer diagnosis, and about two-thirds of these survivors are receiving radiation therapy. Therefore, the late effect of radiation is an area of clinical interest [2]. IR also induces factors that are important in modulating mitochondrial biogenesis, which is related to cell survival: mitochondria have also been reported to be the primary target for radiation-induced apoptosis [3].…”

“…In mammals, muscles make up almost half of body weight, but it is common that they are generally resistant to radiation and are not an important part of body changes following irradiation [19]. However, transient weakness (a type of injury) and metabolic disorders have been observed in animals after irradiation [20], and childhood radiation therapy can cause muscle atrophy, weakness, impaired mobility, and fibrosis [2,21]. There is currently no information about the effects of IR on mitochondrial energy metabolism in skeletal muscle [22].…”