Skeletal muscle methylome-transcriptome disruptions during the onset and progression of colorectal cancer-induced cachexia

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 that dysregulated DNA methylation plays a role in muscle transcriptional alterations mediating cachexia severity. We aimed to describe and integrate the cachexia methylome and transcriptome. We used a time course approach in a mild cachexia model (colon-26, C26) coupled with a severe cachexia genetic model (<i>Apc</i>^Min/+) 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, whereas females were more protected; in severe pathophysiologic phenotypes, the magnitude of change was similar between sexes. A conserved set of inflammation-related genes was dysregulated across cachexia progression and sex, including <i>Osmr</i>, <i>Stat3</i>, and <i>Serpina3n</i>. Epigenetic alterations in both sexes emerged in promoter regions as early as 10 days post-tumor implant in C26, despite a lack of physiologic phenotype and before 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 <i>Runx1</i> and neurodegeneration-related pathways, which may indicate cachexia-mediated denervation. Overall, we provide evidence for the role of epigenetics in cachexia progression and severity and a valuable resource to the cachexia research communities.<b>NEW & NOTEWORTHY</b> Using multi-omics integration, we establish that DNA methylation status likely influences the muscle transcriptome during cancer cachexia, affecting pathways commonly disrupted in cachexia including those associated with neurodegeneration and metabolism. Epigenetic dysregulation occurs early and progresses during the onset and establishment of cancer cachexia, highlighting DNA methylation as a potential therapeutic target to slow or mitigate disease progression.