Study of molecular and metabolic changes in skeletal muscle in response to cancer

  • Author / Creator
    Stretch, Cynthia
  • Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss, wasting of skeletal muscle driven by reduced food intake and abnormal metabolism. Cachexia has a negative impact on quality of life, response to chemotherapy and survival. Cachexia research is undeveloped with respect to understanding molecular changes involved and its classification / diagnostic criteria (there are no clinically useful predictors and diagnostic tests). The purpose of this research was to take advantage of gene expression (transcriptomic) and metabolite (metabolomic) profiling to address these gaps. Patients with cancer consented to provide skeletal muscle biopsy (n=134) for gene expression array or plasma and urine (n=93) for nuclear magnetic resonance spectroscopy and mass spectrometry. Omic data output was examined in relation to different dimensions of cachexia phenotype; gene expression was examined in relation to weight loss, muscle mass and muscle radiation attenuation and metabolites were examined in relation to muscle loss, muscle and fat mass, metabolic rate and food intake. Statistical analysis included standard statistical tests and machine learning methods. Muscle gene expression varied strongly in relation to muscle attenuation, and to a much lesser degree with weight loss and muscle mass. Differential expression suggests low attenuation muscle has persistent inflammation, increased degradation, altered energy metabolism, increased extracellular matrix components and altered growth signalling. Urinary metabolites reflected muscle mass and to a lesser extent fat mass, and could be used to predict muscle mass and rate of muscle loss with 98% and 82% accuracy, respectively. Urinary metabolites related to muscle mass and muscle loss were associated with amino acid and ATP synthesis. Overall, transcriptomics work revealed a molecular signature for low muscle attenuation, which parallels many gene expression changes observed during aberrant muscle repair and metabolic syndrome. This explorative transcriptomic study provides multiple potentially crucial pathways that have yet to be studied in detail in cachexia. Metabolomics work revealed that urine metabolites are most reflective of muscle mass and its change. This work suggests that it may be possible to develop a metabolomics-based tool to assess skeletal muscle mass in cancer. Validation of urine metabolomics to predict muscle mass loss is warranted.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Oncology
  • Supervisor / co-supervisor and their department(s)
    • Baracos, Vickie (Oncology)
  • Examining committee members and their departments
    • Damaraju, Sambasivarao (Oncology)
    • Jagoe, Thomas (Oncology)
    • McCargar, Linda (Agricultural, Food & Nutritional Science)
    • Sawyer, Michael (Oncology)
    • Baracos, Vickie (Oncology)
    • Ball, Ron (Agricultural, Food & Nutritional Science)