Targeting mitochondria by ss-31 ameliorates the whole body energy status in cancer-and chemotherapy-induced cachexia

Objective: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative ca-pacity and low intracellular ATP resulting from abnormal mitochondrial function were described. Methods: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiv-ing chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. Results: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condi-tion (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metab-olome, likely reflecting an improved systemic energy homeostasis. Conclusions: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabo-lism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.