Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia

SIMPLE SUMMARY: Cancer cachexia is a debilitating syndrome, caused by both tumor growth and chemotherapy. The skeletal muscle is one of the main tissues affected during cachexia, presenting with altered metabolism and function, leading to progressive tissue wasting. In the current study we aimed at counteracting cachexia by pharmacologically improving metabolic function with the mitochondria-targeted compound SS-31. Experimental cancer cachexia was obtained using C26-bearing mice either receiving chemotherapy (oxaliplatin plus 5-fluorouracil) or not. SS-31 proved effective in rescuing some of the metabolic impairments imposed by both tumor and chemotherapy in the skeletal muscle and the liver, improving systemic energy control. Unfortunately, such effects were no longer present at late disease stages when refractory cachexia ensued. Overall, we provide evidence of potential new treatments targeting mitochondrial function in order to counteract or delay cancer cachexia. ABSTRACT: Objective: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity 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 receiving 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 condition (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 metabolome, likely reflecting an improved systemic energy homeostasis. Conclusions: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.