Chemoradiation impairs myofiber hypertrophic growth in a pediatric tumor model

Abstract

Pediatric cancer treatment often involves chemotherapy and radiation, where off-target effects can include skeletal muscle decline. The effect of such treatments on juvenile skeletal muscle growth has yet to be investigated. We employed a small animal irradiator to administer fractionated hindlimb irradiation to juvenile mice bearing implanted rhabdomyosarcoma (RMS) tumors. Hindlimb-targeted irradiation (3 × 8.2 Gy) of 4-week-old mice successfully eliminated RMS tumors implanted one week prior. After establishment of this preclinical model, a cohort of tumor-bearing mice were injected with the chemotherapeutic drug, vincristine, alone or in combination with fractionated irradiation (5 × 4.8 Gy). Single myofiber analysis of fast-contracting extensor digitorum longus (EDL) and slow-contracting soleus (SOL) muscles was conducted 3 weeks post-treatment. Although a reduction in myofiber size was apparent, EDL and SOL myonuclear number were differentially affected by juvenile irradiation and/or vincristine treatment. In contrast, a decrease in myonuclear domain (myofiber volume/myonucleus) was observed regardless of muscle or treatment. Thus, inhibition of myofiber hypertrophic growth is a consistent feature of pediatric cancer treatment.

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

“…Juvenile muscle growth requires functioning MuSCs providing for the addition of new myonuclei to myofibres 8 . Previous work using the same RMS plus therapy model showed that treatment‐induced depletion of MuSCs underlies impaired muscle development 5 . Further, RET has been shown to elevate MuSC content, 16 whereas MuSC ablation impairs muscle adaptation to RET 29 .…”

“…The RMS + Tx model was conducted as previously described ( Figure ) 5 . All mice were injected with 100 000 M3‐9‐M cells in sterile phosphate‐buffered saline (PBS) into the left gastrocnemius (RMS + Tx) 17 .…”

Muscle‐specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination

“…All radiation was delivered using a small animal radiation research platform as previously described. 4,5 Briefly, mice were anaesthetized, and fractionated radiation of three doses at 8.2 Gy was administered ~6 days after RMS implantation locally to the lower right limb. Note that standard clinical regimens for individuals afflicted with high-grade RMS utilize extended fractionation schedules for total radiation doses of 35-60 Gy.…”

“…2 However, multifarious direct and indirect effects of radiotherapy can negatively impact tissue growth and maintenance especially in actively growing populations. [3][4][5][6] Longitudinal studies of paediatric cancer survivors demonstrate evidence of accelerated ageing and skeletal muscle decline or sarcopenia, which is typically associated with the geriatric population. 7 About 67% of adult survivors of paediatric cancers experience musculoskeletal frailties, 8 which are characterized by diminished physiological function, muscle loss, 7 reduced strength, 9 increased fatigability, fibrosis, and exercise intolerance, all of which negatively impact quality of life.…”

Insights into muscle stem cell dynamics during postnatal development

“…Our group has recently published two studies investigating the consequences of cancer therapies on juvenile muscle maturation and development [63,78]. In the first study, Paris et al [78] utilized a syngeneic rhabdomyosarcoma (RMS) tumor model. Originating from immature skeletal muscle, RMS is the most common childhood sarcoma [79].…”