title: MicroRNAs-mediated regulation of muscle wasting in cancer-associated cachexia
Creators: name: Borja González, María
Publisher: name: University of Galway
Year: 2024
Subjects: subject: Medicine
subject: Physiology
subject: FOS: Biological sciences
subject: MicroRNAs
subject: Muscle wasting
subject: cachexia
subject: Medicine, Nursing and Health Sciences

description: Cancer-associated cachexia (CAC) affects approximately 70% of cancer patients and is responsible for up to 22% of cancer deaths. CAC is a severe syndrome characterised by significant muscle wasting, systemic inflammation, and metabolic disturbances, which greatly contribute to the increased mortality among cancer patients. MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression. Changes in the expression of specific miRs during cachexia, including those with known roles in muscle function, have been observed. However, there is limited understanding of sex-specific molecular changes during cachexia, early alterations in muscle during tumour development, or the potential of miRs to regulate key signalling pathways involved in cachexia. I hypothesised that modulating miRs levels during cancer cachexia could prevent or slow the progression of muscle wasting associated with cancer. In vivo and in vitro models of cachexia, combined with miR overexpression and inhibition, followed by global and molecular phenotype characterisation, were performed to determine the role of miRs in cancer cachexia. The work in Chapter 3 used global proteomic and transcriptomic approaches to demonstrate sex-specific changes in muscle in an in vivo model of early stages of cachexia at the proteome and transcriptome levels. In males, the main pathways affected were mitochondrial respiration and oxidative phosphorylation, whereas in females, pro-inflammatory pathways were more prominently affected. Mitochondrial function and protein folding pathways were affected in both males and females during early stages of cachexia. These findings are consistent with observations previously demonstrated in the late stages of cachexia in mice and humans. In Chapter 4, the systemic delivery of miR-379-3p during initiation of cachexia, resulted in a partial rescue of muscle mass loss resulting from tumour presence, with a more pronounced effect observed in females. miR-379-3p improved mitochondrial function, particularly in males, and exhibited potential anti-inflammatory effects in females, where it also improved neuromuscular homeostasis markers, for example genes associated with myelination. In Chapter 5 the delivery of miR-26a-5p in vitro preserved myotube size by enhancing mitochondrial biogenesis, reducing apoptosis, and modulating inflammatory pathways. These findings suggested the potential of miR-26a-5p in maintaining muscle function in cachectic conditions and warrant further in vivo experiments. In Chapter 6, I explored a combinatorial miR therapeutic approach through concomitant overexpression of miRs downregulated in muscle of cachectic mice and humans: miR-379-3p, miR-26a-5p, miR-181a-5p, and inhibition of miR overexpressed in muscle of cachectic mice and humans: miR-24. The results from this chapter indicated only modest improvements in muscle preservation and did not necessarily yield synergistic benefits, suggesting that further work is needed to determine optimal combination of miRs and their potential benefit over single miR manipulation. Overall, this research advances our understanding of the molecular drivers of the early stages of cancer cachexia, as well as sex-specific characteristics, providing potential therapeutic candidates with mechanistic involvement in muscle wasting during cancer. Moreover, it demonstrates the potential of miR-379-3p as a therapeutic agent to tackle muscle wasting during cachexia. These findings suggest that early intervention with miR therapies targeting mitochondrial function, apoptosis, and inflammation could mitigate muscle wasting and enhance the quality of life for cancer patients suffering from cachexia. Future research should focus on optimising these therapeutic strategies, considering patient-specific factors such as sex and the stage of disease, and exploring the integration of miR therapies with existing cancer treatments.