Mitochondrial Relationships and Contributions to Muscle Weakness and Wasting during Cancer Cachexia

Cancer-induced cachexia is the on-going loss of skeletal muscle mass and function throughout cancer progression. 20%-80% of cancer patients are predicted to develop cachexia depending on the type and stage of cancer, of which, there is currently no treatment. Current literature on the mechanisms of muscle loss and weakness in cancer have been limiting, especially as it relates to mitochondrial function. Moreover, several experts have suggested the use of cancer cachexia models which replicate the human disease more accurately would be of large utility towards mechanism elucidation and therapy development within this disease.

The focus of this dissertation was to first determine the precise muscle-specific and time-dependent cancer-induced muscle myopathy through two different preclinical models of cancer cachexia. We first used the well-established Colon-26 (C26)-ectopic model of cancer cachexia to characterize skeletal muscle weakness, atrophy and mitochondrial function across time and muscle types. We then used a novel metastatic and orthotopic model of epithelial ovarian cancer (EOC) cachexia to further identify precise cancer-induced skeletal muscle myopathy, once again across time and different muscle types. Finally, to both establish the efficacy of a novel treatment and establish a direct link between cancer-induced skeletal muscle myopathy and mitochondrial function, we administered the mitochondrial-targeted therapeutic SkQ1 to EOC tumour bearing mice.

Our findings reveal that cancer-induced skeletal muscle weakness precedes the development of skeletal muscle atrophy in both the C26-ectopic and EOC-orthotopic models of cancer cachexia. Thus, this dissertation identifies muscle atrophy-independent contributions to skeletal muscle weakness exist in cancer-induced myopathy, a phenomenon yet to be explored. Our findings also demonstrate decreases in mitochondrial respiration and increases in mitochondrial reactive oxygen species are associated with skeletal muscle weakness and atrophy across two preclinical models. Last, treatment with SkQ1 establishes a direct link between mitochondrial function and skeletal muscle weakness independent of atrophy as this mitochondrial-enhancing drug improved force production across various muscles and time. In conclusion, this dissertation identifies a direct relationship between mitochondrial function and cancer-induced weakness. This work supports the future investigation of mitochondrial targeted therapy in cancer cachexia.