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

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. Synopsis In a Drosophila larval eye imaginal disc tumour model of cancer cachexia, this study demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting. Downstream of FOXO, mitochondrial fusion and beta-oxidation are responsible for increased utilisation of muscle lipids, causing loss of muscle integrity. Feeding cachectic flies a diet supplemented with nicotinamide (Vitamin B3), or a high-fat coconut oil diet, which replenished lipids in the muscle, were sufficient to improve muscle integrity. A similar depletion of lipid reserves is observed in muscles of the C-26 mouse cachexia model. Beta-oxidation gene Carnitine palmitoyltransferase 1A (CPT1A, the mammalian homolog of Whd) is negatively correlated with muscle quality in cachectic patients with pancreatic ductal adenocarcinoma. In a Drosophila larval eye imaginal disc tumour model of cancer cachexia, this study demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting.