A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle
Summary: Skeletal muscle dysfunction or reprogramming due to the effects of the cancer secretome is observed in multiple malignancies. Although mouse models are routinely used to study skeletal muscle defects in cancer, because of species specificity of certain cytokines/chemokines in the secretome,...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223006181 |
| _version_ | 1797847676227682304 |
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| author | Ruizhong Wang Brijesh Kumar Poornima Bhat-Nakshatri Aditi S. Khatpe Michael P. Murphy Kristen E. Wanczyk Edward Simpson Duojiao Chen Hongyu Gao Yunlong Liu Emma H. Doud Amber L. Mosley Harikrishna Nakshatri |
| author_facet | Ruizhong Wang Brijesh Kumar Poornima Bhat-Nakshatri Aditi S. Khatpe Michael P. Murphy Kristen E. Wanczyk Edward Simpson Duojiao Chen Hongyu Gao Yunlong Liu Emma H. Doud Amber L. Mosley Harikrishna Nakshatri |
| author_sort | Ruizhong Wang |
| collection | DOAJ |
| description | Summary: Skeletal muscle dysfunction or reprogramming due to the effects of the cancer secretome is observed in multiple malignancies. Although mouse models are routinely used to study skeletal muscle defects in cancer, because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required. Here, we establish simplified multiple skeletal muscle stem cell lines (hMuSCs), which can be differentiated into myotubes. Using single nuclei ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq), we document chromatin accessibility and transcriptomic changes associated with the transition of hMuSCs to myotubes. Cancer secretome accelerated stem to myotube differentiation, altered the alternative splicing machinery and increased inflammatory, glucocorticoid receptor, and wound healing pathways in hMuSCs. Additionally, cancer secretome reduced metabolic and survival pathway associated miR-486, AKT, and p53 signaling in hMuSCs. hMuSCs underwent myotube differentiation when engrafted into NSG mice and thus providing a humanized in vivo skeletal muscle model system to study cancer cachexia. |
| first_indexed | 2024-04-09T18:15:17Z |
| format | Article |
| id | doaj.art-1438aa9d57ba4cedbd600e0d5b03d86c |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-09T18:15:17Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-1438aa9d57ba4cedbd600e0d5b03d86c2023-04-13T04:27:01ZengElsevieriScience2589-00422023-04-01264106541A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscleRuizhong Wang0Brijesh Kumar1Poornima Bhat-Nakshatri2Aditi S. Khatpe3Michael P. Murphy4Kristen E. Wanczyk5Edward Simpson6Duojiao Chen7Hongyu Gao8Yunlong Liu9Emma H. Doud10Amber L. Mosley11Harikrishna Nakshatri12Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; VA Roudebush Medical Center, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; VA Roudebush Medical Center, Indianapolis, IN 46202, USACenter for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USACenter for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USACenter for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USACenter for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; VA Roudebush Medical Center, Indianapolis, IN 46202, USA; Corresponding authorSummary: Skeletal muscle dysfunction or reprogramming due to the effects of the cancer secretome is observed in multiple malignancies. Although mouse models are routinely used to study skeletal muscle defects in cancer, because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required. Here, we establish simplified multiple skeletal muscle stem cell lines (hMuSCs), which can be differentiated into myotubes. Using single nuclei ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq), we document chromatin accessibility and transcriptomic changes associated with the transition of hMuSCs to myotubes. Cancer secretome accelerated stem to myotube differentiation, altered the alternative splicing machinery and increased inflammatory, glucocorticoid receptor, and wound healing pathways in hMuSCs. Additionally, cancer secretome reduced metabolic and survival pathway associated miR-486, AKT, and p53 signaling in hMuSCs. hMuSCs underwent myotube differentiation when engrafted into NSG mice and thus providing a humanized in vivo skeletal muscle model system to study cancer cachexia.http://www.sciencedirect.com/science/article/pii/S2589004223006181Cancer systems biologyCell biologyMolecular biology |
| spellingShingle | Ruizhong Wang Brijesh Kumar Poornima Bhat-Nakshatri Aditi S. Khatpe Michael P. Murphy Kristen E. Wanczyk Edward Simpson Duojiao Chen Hongyu Gao Yunlong Liu Emma H. Doud Amber L. Mosley Harikrishna Nakshatri A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle iScience Cancer systems biology Cell biology Molecular biology |
| title | A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle |
| title_full | A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle |
| title_fullStr | A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle |
| title_full_unstemmed | A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle |
| title_short | A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle |
| title_sort | human skeletal muscle stem myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle |
| topic | Cancer systems biology Cell biology Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223006181 |
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