Author ORCID Identifier:
https://orcid.org/0000-0002-9811-3585
Date of Graduation
9-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Health, Sport and Exercise Science (PhD)
Degree Level
Graduate
Department
Health, Human Performance and Recreation
Advisor/Mentor
Nicholas Greene
Committee Member
Kevin Murach
Third Committee Member
Timothy Muldoon
Fourth Committee Member
Tyrone Washington
Keywords
Atrophy; Biological sex; Epigenetic; Molecular signatures; Muscle loss; Omics integration
Abstract
Cancer cachexia is a wasting syndrome characterized by the loss of skeletal muscle affecting cancer patients’ independence and quality of life. Cancer cachexia affects up to 80% of cancer patients and is responsible for 30-40% of cancer-related deaths. Previous studies have demonstrated sex-specific differences in the onset and progression of cancer cachexia; however, these differences remain underexplored. To date, pharmacological and nutritional interventions are largely ineffective in preventing or reversing cachexia. Chemotherapy, a first-line cancer treatment, is known to trigger cachexia by itself complicating prognosis and therapy response. In addition, epigenetic alterations, such as DNA methylation (DNAm), are known to impact other types of muscle atrophy but remain unexplored in the context of cancer cachexia. Therefore, this dissertation aimed to investigate DNA methylation (DNAm) patterns during the onset, progression, and severity of colorectal cancer cachexia across biological sexes (Aim 1, Chapter 3), and to define how chemotherapeutic treatments interact with cancer to influence muscle atrophy in a sex-specific manner (Aim 2, Chapter 4). To achieve Aim 1, I employed a novel experimental design including: (1) effective chemotherapy (tumor reduction), (2) ineffective chemotherapy (no change in tumor size), and (3) chemotherapy- only, non-cancerous control groups, allowing for the evaluation of cachexia driven by cancer, chemotherapy, or both. I found that while chemotherapy and cancer induce similar phenotypic effects in males, chemotherapy in females exacerbates multi-organ alterations. In addition, my findings suggest muscle wasting in chemotherapy-treated mice may occur through mechanisms distinct from those driven by cancer alone, potentially involving DEPTOR dysregulation. For Aim 2, I utilized transcriptomic and methylomic data, and their integration, from two colorectal cancer cachexia models of varying severity. By analyzing multiple time points, I characterized the molecular progression of cachexia and identified sex-specific differences. Notably, I found that early methylome dysregulation was associated with impaired signaling associated with muscle regeneration and activation of neurodegenerative pathways in both sexes. Overall, this dissertation advances our understanding of the molecular mechanisms underlying muscle wasting during cancer cachexia onset and progression. It also highlights the distinct pathways activated by chemotherapeutic agents in males and females and their differences, underscoring the importance of including female population in cachexia research and for sex- specific preventive and therapeutic strategies.
Citation
Cabrera Ayuso, A. R. (2025). An Integrated Skeletal Muscle Methylome-transcriptome Profile in Pre-clinical Colorectal Cancer Cachexia Models and Chemotherapy Aggravating the Effects of Cachexia. Graduate Theses and Dissertations Retrieved from https://scholarworks.uark.edu/etd/5841
