Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy

Joseph, Josiane; Cho, Dong Seong; Doles, Jason D.

doi:10.3390/metabo8040061

Cited by 24 publications

(26 citation statements)

References 45 publications

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“…Metabolism plays a crucial role in controlling the fate of progenitor cells in tissue development, homeostasis, regeneration, and disease (Lunt & Vander Heiden, 2011;Ryall et al, 2015;Knobloch et al, 2017;Joseph et al, 2018;Pala et al, 2018;Marinkovic et al, 2019). In the skeletal muscle, a variety of nutritional approaches, including caloric restriction, fasting-mimicking drugs, long-term (16 wk) HFD, and amino acid treatments have been applied, displaying different effects on healthy and dystrophic muscle regeneration (Radley-Crabb et al, 2011;Cerletti et al, 2012;Banfi et al, 2018;Juban et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

et al. 2020

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In Duchenne muscular dystrophy (DMD), the absence of the dystrophin protein causes a variety of poorly understood secondary effects. Notably, muscle fibers of dystrophic individuals are characterized by mitochondrial dysfunctions, as revealed by a reduced ATP production rate and by defective oxidative phosphorylation. Here, we show that in a mouse model of DMD (mdx), fibro/adipogenic progenitors (FAPs) are characterized by a dysfunctional mitochondrial metabolism which correlates with increased adipogenic potential. Using high-sensitivity mass spectrometry–based proteomics, we report that a short-term high-fat diet (HFD) reprograms dystrophic FAP metabolism in vivo. By combining our proteomic dataset with a literature-derived signaling network, we revealed that HFD modulates the β-catenin–follistatin axis. These changes are accompanied by significant amelioration of the histological phenotype in dystrophic mice. Transplantation of purified FAPs from HFD-fed mice into the muscles of dystrophic recipients demonstrates that modulation of FAP metabolism can be functional to ameliorate the dystrophic phenotype. Our study supports metabolic reprogramming of muscle interstitial progenitor cells as a novel approach to alleviate some of the adverse outcomes of DMD.

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Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

et al. 2020

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“…Tissues were enzymatically dissociated as described previously. 26 Briefly, muscle tissues were minced and dissociated in 0.2% Collagenase II (ThermoFisher) for 1 h in 37°C. Dissociated cells from muscle tissues were then filtered through 40 μm cell strainer.…”

Section: Single-cell Isolationmentioning

confidence: 99%

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

Cho

Schmitt

Dasgupta

et al. 2020

J cachexia sarcopenia muscle

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Background Persistent loss of skeletal muscle mass and function as well as altered fat metabolism are frequently observed in severe sepsis survivors. Studies examining sepsis-associated tissue dysfunction from the perspective of the tissue microenvironment are scarce. In this study, we comprehensively assessed transcriptional changes in muscle and fat at single-cell resolution following experimental sepsis induction. Methods Skeletal muscle and visceral white adipose tissue from control mice or mice 1 day or 1 month following faecal slurry-induced sepsis were used. Single cells were mechanically and enzymatically prepared from whole tissue, and viable cells were further isolated by fluorescence activated cell sorting. Droplet-based single-cell RNA-sequencing (scRNA-seq; 10× Genomics) was used to generate single-cell gene expression profiles of thousands of muscle and fat-resident cells. Bioinformatics analyses were performed to identify and compare individual cell populations in both tissues. Results In skeletal muscle, scRNA-seq analysis classified 1438 single cells into myocytes, endothelial cells, fibroblasts, mesenchymal stem cells, macrophages, neutrophils, T-cells, B-cells, and dendritic cells. In adipose tissue, scRNA-seq analysis classified 2281 single cells into adipose stem cells, preadipocytes, endothelial cells, fibroblasts, macrophages, dendritic cells, Bcells, T-cells, NK cells, and gamma delta T-cells. One day post-sepsis, the proportion of most non-immune cell populations was decreased, while immune cell populations, particularly neutrophils and macrophages, were highly enriched. Proportional changes of endothelial cells, neutrophils, and macrophages were validated using faecal slurry and cecal ligation and puncture models. At 1 month post-sepsis, we observed persistent enrichment/depletion of cell populations and further uncovered a cell-type and tissue-specific ability to return to a baseline transcriptomic state. Differential gene expression analyses revealed key genes and pathways altered in post-sepsis muscle and fat and highlighted the engagement of infection/inflammation and tissue damage signalling. Finally, regulator analysis identified gonadotropin-releasing hormone and Bay 11-7082 as targets/compounds that we show can reduce sepsis-associated loss of lean or fat mass. Conclusions These data demonstrate persistent post-sepsis muscle and adipose tissue disruption at the single-cell level and highlight opportunities to combat long-term post-sepsis tissue wasting using bioinformatics-guided therapeutic interventions.

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“…In humans, increased BMAT is associated with increased plasma lipids (Scheller et al, 2016); however, studies examining serum lipid levels have shown no difference between mdx and WT mice (Milad et al, 2017). In contrast, mdx mice appear to have defects in expansion of primary adipose progenitor cells in vitro (Joseph et al, 2018), and therefore altered BMAT may also relate to differences in adipose progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

A comparison of the bone and growth phenotype of mdx, mdx:Cmah−/− and mdx:Utrn +/− murine models with the C57BL/10 wild-type mouse

Wood

Suchacki

Hof

et al. 2020

Disease Models &Amp; Mechanisms

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The muscular dystrophy X-linked (mdx) mouse is commonly used as a mouse model of Duchenne muscular dystrophy (DMD). Its phenotype is, however, mild, and other mouse models have been explored. The mdx:Cmah −/− mouse carries a human-like mutation in the Cmah gene and has a severe muscle phenotype, but its growth and bone development are unknown. In this study, we compared male mdx, mdx:Utrn +/− , mdx:Cmah −/− and wild-type (WT) mice at 3, 5 and 7 weeks of age to determine the suitability of the mdx:Cmah −/− mouse as a model for assessing growth and skeletal development in DMD. The mdx:Cmah −/− mice were lighter than WT mice at 3 weeks, but heavier at 7 weeks, and showed an increased growth rate at 5 weeks. Cortical bone fraction as assessed by micro-computed tomography was greater in both mdx and mdx:Cmah −/− mice versus WT mice at 7 weeks. Tissue mineral density was also higher in mdx: Cmah −/− mice at 3 and 7 weeks. Gene profiling of mdx:Cmah −/− bone identified increased expression of Igf1, Igf1r and Vegfa. Both the mdx and mdx:Cmah −/− mice showed an increased proportion of regulated bone marrow adipose tissue (BMAT) but a reduction in constitutive BMAT. The mdx:Cmah −/− mice show evidence of catch-up growth and more rapid bone development. This pattern does not mimic the typical DMD growth trajectory and therefore the utility of the mdx: Cmah −/− mouse for studying growth and skeletal development in DMD is limited. Further studies of this model may, however, shed light on the phenomenon of catch-up growth. This article has an associated First Person interview with the first author of the paper.

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Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy

Cited by 24 publications

References 45 publications

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

A comparison of the bone and growth phenotype of mdx, mdx:Cmah−/− and mdx:Utrn +/− murine models with the C57BL/10 wild-type mouse

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