Affiliation:
1. School of Human Kinetics University of Ottawa Ottawa Ontario Canada
2. Department of Cellular and Molecular Medicine, Regenerative Medicine Program University of Ottawa Ottawa Ontario Canada
Abstract
AbstractBackgroundRhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma that most often develops in children. Chemoradiation therapy is a standard treatment modality; however, the detrimental long‐term skeletal muscle consequences of this therapy in juvenile cancer survivors include muscle atrophy and fibrosis resulting in decreased physical performance. Using a novel model of murine resistance and endurance exercise training, we investigate its role in preventing the long‐term effects of juvenile RMS plus therapy.MethodsFour‐week‐old male (n = 10) and female (n = 10) C57Bl/6J mice were injected with M3‐9‐M RMS cell into the left gastrocnemius with the right limb serving as an internal control (CON). Mice received a systemic vincristine injection and then five doses of 4.8 Gy of gamma radiation localized to the left hindlimb (RMS + Tx). Mice were then randomly divided into either sedentary (SED) or resistance and endurance exercise training (RET) groups. Changes in exercise performance, body composition, myocellular adaptations and the inflammatory/fibrotic transcriptome were assessed.ResultsRET improved endurance performance (P < 0.0001) and body composition (P = 0.0004) compared to SED. RMS + Tx resulted in significantly lower muscle weight (P = 0.015) and significantly smaller myofibre cross‐sectional area (CSA) (P = 0.014). Conversely, RET resulted in significantly higher muscle weight (P = 0.030) and significantly larger Type IIA (P = 0.014) and IIB (P = 0.015) fibre CSA. RMS + Tx resulted in significantly more muscle fibrosis (P = 0.028), which was not prevented by RET. RMS + Tx resulted in significantly fewer mononuclear cells (P < 0.05) and muscle satellite (stem) cells (MuSCs) (P < 0.05) and significantly more immune cells (P < 0.05) than CON. RET resulted in significantly more fibro‐adipogenic progenitors (P < 0.05), a trend for more MuSCs (P = 0.076) than SED and significantly more endothelial cells specifically in the RMS + Tx limb. Transcriptomic changes revealed significantly higher expression of inflammatory and fibrotic genes in RMS + Tx, which was prevented by RET. In the RMS + Tx model, RET also significantly altered expression of genes involved in extracellular matrix turnover.ConclusionsOur study suggests that RET preserves muscle mass and performance in a model of juvenile RMS survivorship while partially restoring cellular dynamics and the inflammatory and fibrotic transcriptome.
Funder
Natural Sciences and Engineering Research Council of Canada
Agencia Nacional de Investigación y Desarrollo
Subject
Physiology (medical),Orthopedics and Sports Medicine
Cited by
6 articles.
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