线粒体
骨骼肌
恶病质
生物
内分泌学
下调和上调
内科学
浪费的
肌萎缩
肌发生
心肌细胞
肌肉萎缩
脂质氧化
细胞生物学
癌症
生物化学
医学
基因
抗氧化剂
作者
Callum Dark,Nazia Ali,Sofya Golenkina,Vaibhav Dhyani,Ronnie Blazev,Benjamin L. Parker,Kate T. Murphy,Gordon S. Lynch,Tarosi Senapati,S. Sean Millard,Sarah M. Judge,Andrew R. Judge,Lopamudra Giri,Sarah M. Russell,Louise Cheng
标识
DOI:10.1038/s44319-024-00102-z
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI