Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy

Sesillo, Francesca Boscolo; Fox, David J.; Sacco, Alessandra

doi:10.1016/j.celrep.2018.12.089

Cited by 23 publications

(17 citation statements)

References 78 publications

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“…Systemic inflammation due to Neu+ tumours may have accelerated skeletal muscle aging process. In this regard, Ccl11 has recently been shown to reduce self‐renewal of MuSC, although the study was done with MuSC that gave rise to rhabdomyosarcoma 49 . It is interesting the Ccl11 has recently been described as an aging factor and is linked to aging‐associated decline in adult neurogenesis and impaired learning and memory 36 .…”

Section: Discussionmentioning

confidence: 99%

Aging‐associated skeletal muscle defects in HER2/Neu transgenic mammary tumour model

Wang

Kumar

Bhat‐Nakshatri

et al. 2020

JCSM Rapid Communications

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Background Loss of skeletal muscle volume and functional limitations are poor prognostic markers in breast cancer patients. Several molecular defects in skeletal muscle including reduced myoblast determination protein 1 (MyoD) levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumour aetiology. Methods We characterized functional and molecular defects of skeletal muscle in mouse mammary tumour virus (MMTV)-Neu (Neu+) mice (n = 6-12), an animal model that represents HER2 + human breast cancer, and compared the results with well-characterized luminal B breast cancer model MMTV-PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and ex vivo muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle-enriched genes and microRNAs as well as circulating cytokines/chemokines were measured. Because nuclear factor-kappaB (NF-κB) pathway plays a significant role in skeletal muscle defects, the ability of NF-κB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined. Results Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared with age and sex-matched wild type mice, Neu+ tumour-bearing mice had lower grip strength (202 ± 6.9 vs. 179 ± 6.8 g grip force, P = 0.0069) and impaired rotarod performance (108 ± 12.1 vs. 30 ± 3.9 s, P < 0.0001), which was consistent with reduced muscle contractibility (P < 0.0001). Skeletal muscle of Neu+ mice (n = 6) contained lower levels of CD82 + (16.2 ± 2.9 vs. 9.0 ± 1.6) and CD54 + (3.8 ± 0.5 vs. 2.4 ± 0.4) muscle stem and progenitor cells (P < 0.05), suggesting impaired capacity of muscle regeneration, which was accompanied by decreased MyoD, p53, and miR-486 expression in muscles (P < 0.05). Unlike PyMT+ mice, which showed skeletal muscle mitochondrial defects including reduced mitochondria levels and peroxisome proliferator-activated receptor gamma co-activator 1 (beta), Neu + mice displayed accelerated aging-associated changes including muscle fibre shrinkage and increased extracellular matrix deposition. Circulating 'aging factor' and cachexia and fibromyalgia-associated chemokine CC motif chemokine ligand 11 (Ccl11) was elevated in Neu+ mice (1439.56 ± 514 vs. 1950 ± 345 pg/mL, P < 0.05). Treatment of Neu+ mice with DMAPT significantly restored grip strength (205 ± 6 g force), rotarod performance (74 ± 8.5 s), reversed molecular alterations associated with skeletal muscle aging, reduced circulating Ccl11 (1083.26 ± 478 pg/mL), and improved animal survival. Conclusions These results suggest that breast cancer subtype has a specific impact on the type of molecular and structural changes in skeletal muscle, which needs to be taken into consideration while designing therapies to reduce breast cancer-induced skeletal muscle loss and functional limitations.

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Section: Discussionmentioning

confidence: 99%

Aging‐associated skeletal muscle defects in HER2/Neu transgenic mammary tumour model

Wang

Kumar

Bhat‐Nakshatri

et al. 2020

JCSM Rapid Communications

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“…, 2017), and there is an intriguing link between dystrophic muscles with prominent fibrosis and the development of muscle progenitor tumorigenesis as rhabdomyosarcoma (Fanzani et al. , 2013; Boscolo Sesillo et al. , 2019).…”

Section: Discussionmentioning

confidence: 99%

Constricted migration modulates stem cell differentiation

Smith

Irianto

Xia

et al. 2019

MBoC

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Tissue regeneration at an injured site depends on proliferation, migration, and differentiation of resident stem or progenitor cells, but solid tissues are often sufficiently dense and constricting that nuclei are highly stressed by migration. In this study, constricted migration of myoblastic cell types and mesenchymal stem cells (MSCs) increases nuclear rupture, increases DNA damage, and modulates differentiation. Fewer myoblasts fuse into regenerating muscle in vivo after constricted migration in vitro, and myodifferentiation in vitro is likewise suppressed. Myosin II inhibition rescues rupture and DNA damage, implicating nuclear forces, while mitosis and the cell cycle are suppressed by constricted migration, consistent with a checkpoint. Although perturbed proliferation fails to explain defective differentiation, nuclear rupture mislocalizes differentiation-relevant MyoD and KU80 (a DNA repair factor), with nuclear entry of the DNA-binding factor cGAS. Human MSCs exhibit similar damage, but osteogenesis increases—which is relevant to bone and to calcified fibrotic tissues, including diseased muscle. Tissue repair can thus be modulated up or down by the curvature of pores through which stem cells squeeze.

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“…Indeed, DMD and mdx muscles are more susceptible to develop rhabdomyosarcoma. In a severe DMD mouse model lacking p53 and affected by telomere shortening, the MuSC pool and rhabdomyosarcoma formation were increased 93 . Along the same line, muscle teratomas from adult mice were found to be rich in cells expressing the satellite cell markers α7-integrin and VCAM1.…”

Section: State Of the Artmentioning

confidence: 99%

Perspectives on skeletal muscle stem cells

et al. 2021

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Skeletal muscle has remarkable regeneration capabilities, mainly due to its resident muscle stem cells (MuSCs). In this review, we introduce recently developed technologies and the mechanistic insights they provide to the understanding of MuSC biology, including the re-definition of quiescence and Galert states. Additionally, we present recent studies that link MuSC function with cellular heterogeneity, highlighting the complex regulation of self-renewal in regeneration, muscle disorders and aging. Finally, we discuss MuSC metabolism and its role, as well as the multifaceted regulation of MuSCs by their niche. The presented conceptual advances in the MuSC field impact on our general understanding of stem cells and their therapeutic use in regenerative medicine.

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Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy

Cited by 23 publications

References 78 publications

Aging‐associated skeletal muscle defects in HER2/Neu transgenic mammary tumour model

Aging‐associated skeletal muscle defects in HER2/Neu transgenic mammary tumour model

Constricted migration modulates stem cell differentiation

Perspectives on skeletal muscle stem cells

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