Investigating the mechanisms underlying cachexia in pulmonary diseases

Hegarty, Karl Joseph

Investigating the mechanisms underlying cachexia in pulmonary diseases

Hegarty, Karl Joseph

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Publication Type:: Thesis
Issue Date:: 2025

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Field	Value	Language
dc.contributor.author	Hegarty, Karl Joseph
dc.date.accessioned	2026-04-13T03:36:10Z
dc.date.available	2026-04-13T03:36:10Z
dc.date.issued	2025
dc.identifier.uri	http://hdl.handle.net/10453/194663
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Cachexia, characterized by skeletal muscle atrophy, is a frequent comorbidity in cancer and pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), asthma, and chronic obstructive pulmonary disease (COPD). Skeletal muscle enables movement but is also a part of the endocrine system and plays a crucial role in maintaining systemic homeostasis. Its dysregulation in cachexia contributes to increased exacerbation rates, reduced quality of life, and worsened prognosis. In COPD, cachexia is associated with up to a 50% decrease in patient survival compared to non-cachectic patients. Currently there are no approved pharmacological interventions that address cachexia, and non-pharmacological interventions like improving diet and exercise can be difficult to implement. This highlights the need to test novel therapies for cachexia for which experimental mouse models of disease could be utilised. .............................................. In conclusion, increased 4E-BP1 expression and decreased rpS6 phosphorylation in the quadriceps suggested alterations in protein balance in cigarette smoke (CS) exposed mice. Furthermore, mitochondrial functions such as complex I proton leak and ADP sensitivity in the gastrocnemius were altered by CS exposure and both H-151 and UA treatments, though the changes were inconsistent between the two models. Collectively, this study demonstrates the potential utility of murine COPD models for investigating cachexia-targeted therapies as mice consistently lost significant gastrocnemius and quadriceps muscle mass with CS exposure. However, it also highlights significant limitations of these models, in particular the rapid, supra-physiological nature of CS induced muscle mass loss and the poor reproducibility of skeletal muscle outcomes such as mitochondrial respiration and mTORC1 signalling measurements. Overall, this suggests that targeting mitochondrial dysfunction and inflammation could still provide therapeutic potential for COPD cachexia and indicates H-151 and UA have limited therapeutic efficacy.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/194663/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2025 Karl Joseph Hegarty
dc.rights	au.edu.uts.lib/cph
dc.title	Investigating the mechanisms underlying cachexia in pulmonary diseases	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Cachexia, characterized by skeletal muscle atrophy, is a frequent comorbidity in cancer and pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), asthma, and chronic obstructive pulmonary disease (COPD). Skeletal muscle enables movement but is also a part of the endocrine system and plays a crucial role in maintaining systemic homeostasis. Its dysregulation in cachexia contributes to increased exacerbation rates, reduced quality of life, and worsened prognosis. In COPD, cachexia is associated with up to a 50% decrease in patient survival compared to non-cachectic patients. Currently there are no approved pharmacological interventions that address cachexia, and non-pharmacological interventions like improving diet and exercise can be difficult to implement. This highlights the need to test novel therapies for cachexia for which experimental mouse models of disease could be utilised. .............................................. In conclusion, increased 4E-BP1 expression and decreased rpS6 phosphorylation in the quadriceps suggested alterations in protein balance in cigarette smoke (CS) exposed mice. Furthermore, mitochondrial functions such as complex I proton leak and ADP sensitivity in the gastrocnemius were altered by CS exposure and both H-151 and UA treatments, though the changes were inconsistent between the two models. Collectively, this study demonstrates the potential utility of murine COPD models for investigating cachexia-targeted therapies as mice consistently lost significant gastrocnemius and quadriceps muscle mass with CS exposure. However, it also highlights significant limitations of these models, in particular the rapid, supra-physiological nature of CS induced muscle mass loss and the poor reproducibility of skeletal muscle outcomes such as mitochondrial respiration and mTORC1 signalling measurements. Overall, this suggests that targeting mitochondrial dysfunction and inflammation could still provide therapeutic potential for COPD cachexia and indicates H-151 and UA have limited therapeutic efficacy.

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http://hdl.handle.net/10453/194663