Obesity Exacerbates Myosteatosis And Alters Lipid Droplet-Mitochondria Contact In A Murine Model Of Cancer Cachexia

Cancer cachexia is the unintentional loss of lean mass and directly contributes to functional dependency, poor treatment outcomes, and decreased survival in cancer patients. While obesity and cachexia are at opposite ends of the weight spectrum these pathologies share some underlying perturbations (i.e. myosteatosis and mitochondrial dysfunction) that may exacerbate functional decrements when these morbidities co-occur. Further, it is suggested lipid droplet-mitochondrial interactions regulate metabolic health and homeostasis of skeletal muscle. PURPOSE: To investigate the impact of obesity on cancer-induced skeletal muscle function and mass loss, intramyocellular lipid droplet content and morphology, and lipid droplet-mitochondrial interactions using a murine model of cancer cachexia. METHODS: Lean and obese C57/BL6 male mice (n = 49) were implanted with LLC cells [106] in the right flank or underwent sham surgery. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus) and histology (tibialis anterior) 25 days following implantation or sham surgery. Cage activity was assessed at day 24. Generalized linear models were used to assess statistical differences (p < .05). RESULTS: There were similar decreases in body weight (-Δ12%; p < .001) and muscle mass (-Δ21%; p < 0.001) in lean/obese LLC mice. Volitional cage activity was reduced in obese LLC mice compared to lean LLC mice (-39%, p < 0.0001). TEM analysis unveiled obese LLC mice had greater intramyocellular lipid droplet size and number. Further, greater oil-red o staining (39%; p = 0.0002) in obese LLC mice compared to their lean counterparts was also observed. Preliminary morphological analyses of lipid droplets show altered morphometrics (i.e. roundness, sphericity, perimeter, etc.) and evidence of altered lipid droplet-mitochondria contact in obese cachectic muscle. CONCLUSIONS: These data demonstrate obese mice were not protected against muscle and function loss and have exacerbated cancer-induced myosteatosis. Interestingly, lipid droplet morphology and lipid droplet-mitochondrial contact were also altered in obese cachectic muscle indicating decrements in muscle mass and function may, in part, be due to perturbations in lipid homeostasis and lipid droplet-mitochondria interactions. F31PA21051 (TDC); U01CA272977 (EAM)