Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome

Pawlikowski, Bradley; Betta, Nicole Dalla; Elston, Tiffany; Williams, Darian A.; Olwin, Bradley B.

doi:10.1038/s41598-018-22342-5

Cited by 15 publications

(9 citation statements)

References 74 publications

(72 reference statements)

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“…Surprisingly, we also found that ubiquitination and histone acetylation was presented in all monosomies. For ubiquitination, few studies have reported that ubiquitination is present in trisomy 18 and trisomy 21 [7,40], which is not consistent with us. No similar studies investigated this pathway in monosomies, and therefore it is di cult for us to discuss with other studies.…”

Section: Discussioncontrasting

confidence: 92%

Are there common mechanisms of aneuploidy-related abortion and defects in fetus?

Xie

Lü

Huang

et al. 2020

Preprint

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Background: Monosomies and trisomies, as the most common aneuploid abnormalities, are the leading causes of miscarriages and fetal defects in humans. Although there is evidence suggested that aneuploid may have some common aspects, their common mechanism still remains unclear. This studies objective was to explore the common mechanism of monosomies and trisomies, with a purpose to identify some critical biomarkers and pathway so as to early diagnosis and effective therapy.Methods: We obtained the mRNA expression profile of GSE114559 including 101 samples data from GEO database. These data include normal, every monosomic, and trisomic transcriptome. We conducted Limma analysis by using the adj. p<0.05 and |FC|>1 criteria to identify all monosomy-related, trisomy-related differentially expressed genes (DEGs), and also to found their overlapping DEGs through Venn diagram. We then performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses, protein-protein interaction(PPI) network analysis to find the functional, pathways and hub genes in these DEGs. We carried out weighted correlation network analysis (WGCNA) to further detect the candidate genes and pathways related to all DEGs and their overlappling DEGs. Finally, we further used qPCR to certify pathological change of specific genes. Results: We identified all monosomy-related, trisomy-related DEGs, and their overlapping DEGs which were enriched by spliceosome, thyroid hormone, infection-related genes and signalling pathways. We also found that epigenetic related pathways were significantly enriched in the DEGs of monosomies by GO, KEGG. We explode the hub gene and module in the DEGs of monosomies and the overlapping DEGs by PPI. Then, we found that spliceosome, thyroid hormone, infection-related genes and signalling pathways were enriched in all DEGs group and the overlapping DEGs group by weighted correlation network analysis (WGCNA). Finally, we certified some hub gene in the trisomy 21, 47, XYY samples from clinical patients by qPCR which were consistent with results of PPI analysis.Conclusion: Our study indicates the potential common mechanism underlining spliceosome, thyroid hormone and infection-related signalling pathways for both monosomies and trisomies, and the mechanism underling epigenetic for monosomies.

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Section: Discussioncontrasting

confidence: 92%

Are there common mechanisms of aneuploidy-related abortion and defects in fetus?

Xie

Lü

Huang

et al. 2020

Preprint

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“…The Ts65Dn mouse, the best characterized and the most commonly used model of DS, shows increased OS (lipid peroxidation and protein carbonylation) and mitochondrial dysfunction in the hippocampus and cortex [77][78][79][80][81][82][83], that affects brain structure and function [75]. Although, to the best of our knowledge, oxidative DNA damage has not been studied in the brain of this model, it has been demonstrated that other cell types such as satellite cells of skeletal myofibers and hematopoietic stem cells accumulate oxidative DNA damage and prematurely develop a senescent phenotype in the Ts65Dn mouse [84][85][86]. This model also shows a high density of cells with an OS-associated senescent phenotype in different areas of the hippocampus (CA1, CA3, GCL, and SGZ), cortex, and medial septum [82,87,88].…”

Section: Brain Oxidative and Mitochondrial Profile In Mouse Models Of Dsmentioning

confidence: 91%

Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials

Revilla

Martı́nez-Cué

2020

Antioxidants

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There is currently no effective pharmacological therapy to improve the cognitive dysfunction of individuals with Down syndrome (DS). Due to the overexpression of several chromosome 21 genes, cellular and systemic oxidative stress (OS) is one of the most important neuropathological processes that contributes to the cognitive deficits and multiple neuronal alterations in DS. In this condition, OS is an early event that negatively affects brain development, which is also aggravated in later life stages, contributing to neurodegeneration, accelerated aging, and the development of Alzheimer’s disease neuropathology. Thus, therapeutic interventions that reduce OS have been proposed as a promising strategy to avoid neurodegeneration and to improve cognition in DS patients. Several antioxidant molecules have been proven to be effective in preclinical studies; however, clinical trials have failed to show evidence of the efficacy of different antioxidants to improve cognitive deficits in individuals with DS. In this review we summarize preclinical studies of cell cultures and mouse models, as well as clinical studies in which the effect of therapies which reduce oxidative stress and mitochondrial alterations on the cognitive dysfunction associated with DS have been assessed.

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“…However, an intriguing lack of obvious functional deficit in the Ts65Dn skeletal muscle has been shown (Cowley et al, 2012). The limited number of morphological studies on the Ts65Dn locomotor muscles reports no difference in the proportion of myofiber types or myofiber size in the hindlimb of trisomic versus euploid animals (Cowley et al, 2012(Cowley et al, , 2017Pawlikowski et al, 2018). From the metabolic point of view, microarray analysis identified alterations in pathways involved in glucose and fat metabolism, as well as ATP biosynthesis, indicating a possible limitation of mitochondrial function in the soleus muscle of Ts65Dn mice (Cowley et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Combined Microscopic and Metabolomic Approach to Characterize the Skeletal Muscle Fiber of the Ts65Dn Mouse, A Model of Down Syndrome

et al. 2020

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Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome

Cited by 15 publications

References 74 publications

Are there common mechanisms of aneuploidy-related abortion and defects in fetus?

Are there common mechanisms of aneuploidy-related abortion and defects in fetus?

Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials

Combined Microscopic and Metabolomic Approach to Characterize the Skeletal Muscle Fiber of the Ts65Dn Mouse, A Model of Down Syndrome

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