Dark, C., Ali, N., Golenkina, S., Dhyani, V., Blazev, R., Parker, B.L., Murphy, K.T., Lynch, G.S., Senapati, T., Millard, S.S., Judge, S.M., Judge, A.R., Giri, L., Russell, S.M., Cheng, L.Y. (2024). Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model.  EMBO Rep. 25(4): 1835--1858.

FBrf0259284

Research paper

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.

PMC11014992 (PMC) (EuropePMC)