A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle
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
Affiliations
Ruizhong Wang
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Brijesh Kumar
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Poornima Bhat-Nakshatri
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Aditi S. Khatpe
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Michael P. Murphy
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; VA Roudebush Medical Center, Indianapolis, IN 46202, USA
Kristen E. Wanczyk
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; VA Roudebush Medical Center, Indianapolis, IN 46202, USA
Edward Simpson
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Duojiao Chen
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Hongyu Gao
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Yunlong Liu
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Emma H. Doud
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Amber L. Mosley
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Harikrishna Nakshatri
Department 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 author
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.
