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A novel transplantable model of lung cancer associated tissue loss and disrupted muscle regeneration

View ORCID ProfilePaige C Arneson, Alexandra M Ducharme, Jason D Doles
doi: https://doi.org/10.1101/852442
Paige C Arneson
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, 55905 USA, Mayo Clinic, Rochester, Minnesota.
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  • ORCID record for Paige C Arneson
Alexandra M Ducharme
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, 55905 USA, Mayo Clinic, Rochester, Minnesota.
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Jason D Doles
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, 55905 USA, Mayo Clinic, Rochester, Minnesota.
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  • For correspondence: doles.jason@mayo.edu
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ABSTRACT

Background Cancer-associated muscle wasting (CAW), a symptom of cancer cachexia, is associated with approximately 20% of lung cancer deaths, and remains poorly characterized on a mechanistic level. Current animal models for lung cancer-associated cachexia are limited in that they: 1) primarily employ flank transplantation methods, 2) have short survival times not reflective of the patient condition, and 3) are typically performed in young mice not representative of mean patient age. This study investigates a new model for lung cancer-associated cachexia that can address these issues and also implicates muscle regeneration as a contributor to CAW.

Methods We used tail vein injection as a method to introduce tumor cells that seed primarily in the lungs of mice. Body composition of tumor bearing mice was longitudinally tracked using NMR-based, echo magnetic resonance imaging (echoMRI). These data were combined with histological and molecular assessments of skeletal muscle to provide a complete analysis of muscle wasting.

Results In this new lung CAW model we observed 1) progressive loss in whole body weight, 2) progressive loss of lean and fat mass, 3) a circulating cytokine/inflammatory profile similar to that seen in other models of CAW, 4) histological changes associated with muscle wasting, and 5) molecular changes in muscle that implicate suppression of muscle repair/regeneration. Finally, we show that survival can be extended without lessening CAW by titrating injected cell number.

Conclusions Overall, this study describes a new model of CAW that could be useful for further studies of lung cancer-associated wasting and accompanying changes in the regenerative capacity of muscle. Additionally, this model addresses many recent concerns with existing models such as immunocompetence, tumor location, and survival time.

Footnotes

  • Added supplemental figure 1 to show heart histopathology, new figure 2 and accompanying supplemental figure 2 focused on transcriptional profiling of muscle, supplemental figure 3 grip strength assessment of mice, and supplemental figure 4 individual animals' longitudinal body composition data. Results and methods sections were updated to reflect this change.

  • LIST OF ABBREVIATIONS

    CAW
    Cancer associated muscle wasting
    LLC
    Lewis lung carcinoma
    CLN
    Centrally-located nuclei
    TA
    Tibialis Anterior
    qPCR
    quantitative polymerase chain reaction
    echoMRI
    echo magnetic resonance imaging
    H&E
    Hematoxylin and Eosin
    DAPI
    4′,6-diamidino-2-phenylindole
    RNAseq
    Ribonucleic acid sequencing
    PCA
    Principle Component Analysis
    GR
    Gastrocnemius
    SEM
    Standard Error of the Mean
    SD
    Standard Deviation
    TNFα
    Tumor Necrosis Factor Alpha
    IL6
    Interleukin 6
    GEMMs
    Genetically Engineered Mouse Models
    IACUC
    Institutional Animal Care and Use Committee
    LIX
    C-X-C Motif Ligand 5
    VEGF
    Vascular Endothelial Growth Factor
    Trim63
    Muscle RING Finger 1 (MuRF1)
    Fbxo32
    F-box Only Protein 32
    Pax7
    Paired Box 7
    MyoD1
    Myogenic Differentiation 1
    NIH
    National Institutes of Health
    NIAMS
    National Institute of Arthritis and Musculoskeletal and Skin Diseases
    NCI
    National Cancer Institute
    RSTP
    Regenerative Sciences Training Program
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted February 04, 2020.
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    A novel transplantable model of lung cancer associated tissue loss and disrupted muscle regeneration
    Paige C Arneson, Alexandra M Ducharme, Jason D Doles
    bioRxiv 852442; doi: https://doi.org/10.1101/852442
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    A novel transplantable model of lung cancer associated tissue loss and disrupted muscle regeneration
    Paige C Arneson, Alexandra M Ducharme, Jason D Doles
    bioRxiv 852442; doi: https://doi.org/10.1101/852442

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