Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model

Dark, C; Ali, N; Golenkina, S; Dhyani, V; Blazev, R; Parker, BL; Murphy, KT; Lynch, GS; Senapati, T; Millard, SS; Judge, SM; Judge, AR; Giri, L; Russell, SM; Cheng, LY

Author(s): Dark, C; Ali, N; Golenkina, S; Dhyani, V; Blazev, R; Parker, BL; Murphy, KT; Lynch, GS; Senapati, T; Millard, SS; Judge, SM; Judge, AR; Giri, L; Russell, SM; Cheng, LY;
Details: Publication Year 2024-04,Volume 25,Issue #4,Page 1835-1858
Journal Title: EMBO Reports
Publication Type: Research article
Abstract: Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.
Publisher: EMBO Press
Keywords: Mice; Animals; Humans; Cachexia/etiology/metabolism; Drosophila/metabolism; Mitochondrial Dynamics; Muscular Atrophy/pathology; Muscle, Skeletal/metabolism; *Colonic Neoplasms/metabolism; *Insulins/metabolism; Lipids; Insulin-Like Growth Factor Binding Proteins/metabolism; *Drosophila Proteins/genetics/metabolism; Drosophila; Cachexia; Lipid Metabolism; Muscle
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s44319-024-00102-z
Open Access at Publisher's Site: https://doi.org/10.1038/s44319-024-00102-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-04 04:51:20

Last Modified: 2024-07-04 04:51:28