Abstract
Advanced colorectal cancer (CRC) is often accompanied by development of liver metastases (LMs) and skeletal muscle wasting (i.e., cachexia). Despite plaguing the majority of CRC patients, cachexia remains unresolved. By using mice injected with Colon-26 mouse tumors, either subcutaneously (s.c.; C26) or intrasplenically to mimic hepatic dissemination of cancer cells (mC26), here we aimed to further characterize functional, molecular, and metabolic effects on skeletal muscle and examine whether LMs exacerbate CRC-induced cachexia. C26-derived LMs were associated with progressive loss of body weight, as well as with significant reductions in skeletal muscle size and strength, in line with reduced phosphorylation of markers of protein anabolism and enhanced protein catabolism. mC26 hosts showed prevalence of fibers with glycolytic metabolism and enhanced lipid accumulation, consistent with abnormalities of mitochondrial homeostasis and energy metabolism. In a comparison with mice bearing s.c. C26, cachexia appeared exacerbated in the mC26 hosts, as also supported by differentially expressed pathways within skeletal muscle. Overall, our model recapitulates the cachectic phenotype of metastatic CRC and reveals that formation of LMs resulting from CRC exacerbate cancer-induced skeletal muscle wasting by promoting differential gene expression signatures.
Authors
Joshua R. Huot, Leah J. Novinger, Fabrizio Pin, Ashok Narasimhan, Teresa A. Zimmers, Thomas M. O’Connell, Andrea Bonetto
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