Date of Graduation
8-2024
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
Greene, Nicholas P.
Committee Member
Esser, Karyn
Second Committee Member
Murach, Kevin A.
Third Committee Member
Washington, Tyrone A.
Fourth Committee Member
Rosa-Caldwell, Megan
Keywords
Atrophy; Biological sex; Cancer; Mitochondria; Muscle
Abstract
Cancer Cachexia (CC) is a multifactorial and complex syndrome affecting up to 80% of cancer patients and contributing to approximately 40% of cancer-related deaths. Given its relationship with patients' quality of life and prognosis, there has been increasing emphasis on understanding the underlying mechanisms of CC using pre-clinical models. However, the mechanisms of cachexia vary depending on several factors, including tumor type, model, and biological variables such as sex. RNA-sequencing technology is a crucial tool for investigating CC heterogeneity, enabling the analysis of the transcriptome across different models, conditions, and sexes using publicly available data. Aim 1 of this dissertation leverages RNA-sequencing to compare skeletal muscle transcriptional alterations in males and females during early and late stages of CC across commonly used models: Lewis Lung Carcinoma (LLC), Pancreatic KPC, Colon-C26, and colorectal ApcMin/+ from our own, and publicly available data sets. The findings reveal that initial responses to tumor burden are highly heterogeneous between models and sexes, whereas later responses become more homogeneous, particularly in female tumor-bearing mice. When clustering models and sexes to explore the transcriptional progression of CC, I identified that dysregulations in pathways associated with the proteasome, mitophagy, autophagy, and metabolism are conserved from early to late-stage transcriptional responses. These findings highlight the need for model, and sex-specific early interventions against CC. In parallel, previous studies on mitochondrial dysfunction in CC, particularly in LLC-bearing mice, showed that the downregulation of the mitochondrial fusion protein OPA1 and the induction of the mitophagy protein BNIP3 contribute to muscle deterioration. We hypothesize that overexpressing OPA1 and inhibiting BNIP3 can improve outcomes in LLC-induced CC. For Aims 2 and 3, I utilized pharmacological and transgenic OPA1 overexpression, and global BNIP3 knockout (KO) models to assess the therapeutic potential of modulating mitochondrial dynamics and turnover systems against skeletal muscle detriments in CC. The results indicate that restoring mitochondrial dynamics balance through OPA1 induction, but not BNIP3 KO, attenuated cachectic outcomes in mice, regardless of biological sex. The benefits of OPA1 are attributed, at least in part, to the restoration of fusion and fission balance and the increase in calcium channel content. This is further supported by the lower fusion-to-fission ratios observed in BNIP3 KO animals, which did not mitigate CC. We propose that a controlled, combined, and timed intervention is necessary to explore the benefits of mitophagy suppression, particularly when mitochondrial dynamics balance is first restored in skeletal muscle. Overall, my dissertation advances our understanding of the heterogeneity in CC transcriptional initiation in skeletal muscle and identifies conserved mechanisms impacted across various models and sexes during CC progression. Additionally, it highlights the potential of targeting mitochondrial fusion as a beneficial strategy against CC, irrespective of sex, and underscores the importance of further investigating combined and timed mitochondrial interventions for combating CC.
Citation
Morena Clark, F. (2024). Cancer Heterogeneity and Mitochondrial-Targeted Therapies in Cancer Cachexia. Graduate Theses and Dissertations Retrieved from https://scholarworks.uark.edu/etd/5467
