Radiation-Induced Damage to Prepubertal Pax7+ Skeletal Muscle Stem Cells Drives Lifelong Deficits in Myofiber Size and Nuclear Number

Bachman, John F.; Blanc, R; Paris, Nicole D.; Kallenbach, Jacob G.; Johnston, Carl J.; Hernady, Eric; Williams, Jacqueline P.; Chakkalakal, Joe V.

doi:10.1016/j.isci.2020.101760

Cited by 29 publications

(68 citation statements)

References 74 publications

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“…To evaluate transcriptomic changes in skeletal muscle across our experimental groups, we performed RNA-sequencing analysis. We previously published the transcriptomic effects of paediatric radiation alone (GSE160064), 5 S1).…”

Section: Up-regulated Inflammatory and Fibrotic Gene Expression After Paediatric Radiotherapymentioning

confidence: 99%

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

Kallenbach

Bachman

Paris

et al. 2022

J cachexia sarcopenia muscle

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Background As paediatric cancer survivors are living into adulthood, they suffer from the age-related, accelerated decline of functional skeletal muscle tissue, termed sarcopenia. With ionizing radiation (radiotherapy) at the core of paediatric cancer therapies, its direct and indirect effects can have lifelong negative impacts on paediatric growth and maintenance of skeletal muscle. Utilizing our recently developed preclinical rhabdomyosarcoma mouse model, we investigated the late effects of paediatric radiation treatment on skeletal muscles from late adolescent (8 weeks old) and middle-aged (16 months old) mice. Methods Paediatric C57BL/6J male mice (3 weeks old) were injected with rhabdomyosarcoma cells into their right hindlimbs, and then fractionated irradiation (3 × 8.2 Gy) was administered to those limbs at 4 weeks old to eliminate the tumours. Radiation-alone and tumour-irradiated mice were assessed at either 8 weeks (3 weeks post-irradiation) or 16 months (14 months post-irradiation) of age for muscle physiology, myofibre characteristics, cell loss, histopathology, fibrosis, inflammatory gene expression, and fibrotic gene expression. Results Mice that received only paediatric radiation demonstrated reduced muscle mass (À17%, P < 0.001), muscle physiological function (À25%, P < 0.01), muscle contractile kinetics (À25%, P < 0.05), satellite cell number (À45%, P < 0.05), myofibre cross-sectional area (À30%, P < 0.0001), and myonuclear number (À17%, P < 0.001). Paediatric radiation increased inflammatory gene expression, increased fibrotic gene expression, and induced extracellular matrix protein deposition (fibrosis) with tumour elimination exacerbating some phenotypes. Paediatric tumour-eliminated mice demonstrated exacerbated deficits to function (À20%, P < 0.05) and myofibre size (À17%, P < 0.001) in some muscles as well as further increases to inflammatory and fibrotic gene expression. Examining the age-related effects of paediatric radiotherapy in middle-aged mice, we found persistent myofibre atrophy (À20%, P < 0.01), myonuclear loss (À18%, P < 0.001), up-regulated inflammatory and fibrotic signalling, and lifelong fibrosis. Conclusions The results from this paediatric radiotherapy model are consistent and recapitulate the clinical and molecular features of accelerated sarcopenia, musculoskeletal frailty, and radiation-induced fibrosis experienced by paediatric cancer survivors. We believe that this preclinical mouse model is well poised for future mechanistic insights and therapeutic interventions that improve the quality of life for paediatric cancer survivors.

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Section: Up-regulated Inflammatory and Fibrotic Gene Expression After Paediatric Radiotherapymentioning

confidence: 99%

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

Kallenbach

Bachman

Paris

et al. 2022

J cachexia sarcopenia muscle

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“…Second, mice have a rapidly developing musculoskeletal system, and mice are relatively inexpensive, which makes them an economic choice for large sample size studies 27 . Various groups have used mouse models of muscle stem cell depletion to examine the contribution to sarcopenia‐related phenotypes 28–31 . Among them, Liu et al 31 .…”

Section: The Importance Of Mouse Models Of Sarcopeniamentioning

confidence: 99%

Mouse models of sarcopenia: classification and evaluation

Xie

Dong-sheng

et al. 2021

J cachexia sarcopenia muscle

132

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Sarcopenia is a progressive and widespread skeletal muscle disease that is related to an increased possibility of adverse consequences such as falls, fractures, physical disabilities and death, and its risk increases with age. With the deepening of the understanding of sarcopenia, the disease has become a major clinical disease of the elderly and a key challenge of healthy ageing. However, the exact molecular mechanism of this disease is still unclear, and the selection of treatment strategies and the evaluation of its effect are not the same. Most importantly, the early symptoms of this disease are not obvious and are easy to ignore. In addition, the clinical manifestations of each patient are not exactly the same, which makes it difficult to effectively study the progression of sarcopenia. Therefore, it is necessary to develop and use animal models to understand the pathophysiology of sarcopenia and develop therapeutic strategies. This paper reviews the mouse models that can be used in the study of sarcopenia, including ageing models, genetically engineered models, hindlimb suspension models, chemical induction models, denervation models, and immobilization models; analyses their advantages and disadvantages and application scope; and finally summarizes the evaluation of sarcopenia in mouse models.

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“…103,104 An emerging body of pre-clinical evidence indicates that irradiation-induced satellite cell depletion impairs the response to hypertrophic stimuli. 104,105 Further, it appears as though the impact of radiation on skeletal muscle morphology might be dose dependent and influenced by fibre type. In 2014, Hardee et al demonstrated muscle protein and RNA content were reduced with a single 16 Gy dose of radiation, but not with four fractionated doses of 4 Gy.…”

Section: Radiotherapymentioning

confidence: 99%

“…Long-term follow ups of individuals who have received treatment for child/young adult cancer reveal persistent impairments in muscular function and tissue decline. 105 However, much less is known of the persistent and/or late effects of cancer and its therapies on signalling pathways once treatment has finished. In adult cancers, untangling the impact of natural ageing, diet, and inactivity on these pathways, vs. the sustained, or late effects of treatments is difficult.…”

Section: How Long Aberrations In Muscle Signalling and Pathology Persist After Treatmentmentioning

confidence: 99%

Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials

Fairman

Lønbro

Cardaci

et al. 2021

JCSM Rapid Communications

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Background Low muscle in cancer is associated with an increase in treatment-related toxicities and is a predictor of cancer-related and all-cause mortality. The mechanisms of cancer-related muscle loss are multifactorial, including anorexia, hypogonadism, anaemia, inflammation, malnutrition, and aberrations in skeletal muscle protein turnover and metabolism. Methods In this narrative review, we summarise relevant literature to (i) review the factors influencing skeletal muscle mass regulation, (ii) provide an overview of how cancer/treatments negatively impact these, (iii) review factors beyond muscle signalling that can impact the ability to participate in and respond to an exercise intervention to counteract muscle loss in cancer, and (iv) provide perspectives on critical areas of future research. Results Despite the well-known benefits of exercise, there remains a paucity of clinical evidence supporting the impact of exercise in cancer-related muscle loss. There are numerous challenges to reversing muscle loss with exercise in clinical cancer settings, ranging from the impact of cancer/treatments on the molecular regulation of muscle mass, to clinical challenges in responsiveness to an exercise intervention. For example, tumour-related/treatmentrelated factors (e.g. nausea, pain, anaemia, and neutropenia), presence of comorbidities (e.g. diabetes, arthritis, and chronic obstructive pulmonary disease), injuries, disease progression and bone metastases, concomitant medications (e.g., metformin), can negatively affect an individual's ability to exercise safely and limit subsequent adaptation. Conclusions This review identifies numerous gaps and oppportunities in the area of low muscle and muscle loss in cancer. Collaborative efforts between preclinical and clinical researchers are imperative to both understanding the mechanisms of atrophy, and develop appropriate therapeutic interventions.

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Radiation-Induced Damage to Prepubertal Pax7+ Skeletal Muscle Stem Cells Drives Lifelong Deficits in Myofiber Size and Nuclear Number

Cited by 29 publications

References 74 publications

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

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

Mouse models of sarcopenia: classification and evaluation

Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials

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