Increased myocellular lipid and IGFBP‐3 expression in a pre‐clinical model of pancreatic cancer‐related skeletal muscle wasting

Background Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which i...

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Published in:Journal of cachexia, sarcopenia and muscle sarcopenia and muscle, 2021-06, Vol.12 (3), p.731-745
Main Authors: Cole, Calvin L., Bachman, John F., Ye, Jian, Murphy, Joseph, Gerber, Scott A., Beck, Christopher A., Boyce, Brendan F., Muthukrishnan, Gowrishankar, Chakkalakal, Joe V., Schwarz, Edward M., Linehan, David
Format: Article
Language:English
Subjects:
Animals
Cachexia - etiology
Cancer therapies
Cytokines
Disease Models, Animal
Failure to thrive
Female
Humans
Insulin-Like Growth Factor Binding Protein 3
Metastasis
Mice
Mice, Inbred C57BL
Mortality
Murine model
Muscle, Skeletal
Musculoskeletal system
Myocellular lipid
Original
Pancreatic cancer
Pancreatic Neoplasms - complications
Quality of Life
Skeletal muscle wasting
Tumor necrosis factor-TNF
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Summary:Background Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model. Methods Female C57BL/6J mice 6–8 weeks of age underwent orthotopic injection with KCKO‐luc tumour cells. Solid tumour was verified on Day 5, post‐tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual‐energy X‐ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of ‘failure to thrive’. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction. Results We found a strong correlation between primary tumour size and survival (r2 = 0.83, P 
ISSN:2190-5991
2190-6009
DOI:10.1002/jcsm.12699