Integrated Muscle Multi-Omics in Cancer Cachexia - Supplemental files

Cancer cachexia is a wasting condition, primarily affecting skeletal muscle, impairing patients’ quality of life, prognosis, and survival. The molecular triggers are incompletely defined but given prior evidence for epigenetic plasticity in muscle, we speculate dysregulated DNA methylation plays a role in muscle transcriptional alterations mediating cachexia severity. We used a time course approach in a mild cachexia model (Colon-26, C26) coupled with a severe cachexia genetic model (ApcMin/+) in both biological sexes to assess the methylome across degrees of cachexia pathology. The muscle methylome and transcriptome were analyzed separately and subsequently integrated using a computational technique to infer epigenetic control of gene expression. Male mice exhibited widespread disruptions to the transcriptome across time points while females were more protected; in severe pathophysiologic phenotypes, the magnitude of change was similar between sexes. A conserved set of inflammation-related genes were dysregulated across cachexia progression and sex, including Osmr, Stat3, and Serpina3n. Epigenetic alterations in promoter regions emerged as early as 10 days post tumor implant in C26 despite a lack of physiologic phenotype and prior to the transcriptome disruptions. Our integration analysis suggests methylome alterations as a mechanism of cachexia pathophysiology in severe phenotypes. A conserved feature across -omics layers, sexes, and conditions was dysregulated Runx1 and neurodegeneration-related pathways, which may indicate cachexia-mediated denervation. Overall, we provide evidence for the role of epigenetics in cachexia progression and severity, providing potential new therapeutic targets, and a valuable resource to the skeletal muscle and cachexia research communities.