Article Title



Thomas D. Cardaci, Brandon N. VanderVeen, Sierra J. McDonald, Brooke M. Bullard, Sarah S. Madero, Kandy T. Velazquez, FACSM, E. Angela Murphy. University of South Carolina School of Medicine, Columbia, SC.

BACKGROUND: Cancer cachexia is the unintentional loss of lean mass and directly contributes to functional dependency, poor treatment outcomes, and decreased survival in cancer patients. Obesity has been suggested to protect against the severity of cachexia due to having ‘more to spare’; however, mechanistic support is lacking to promote obesity’s benefit. Further, obesity increases cancer risk contributing to the likelihood that cancer patients will be overweight or obese. Thus, the purpose of this study is to investigate the impact of obesity on cancer-induced skeletal muscle loss and function, survival, along with mitochondrial dysfunction and loss using the Lewis Lung Carcinoma (LLC) model of cancer cachexia. METHODS: Lean and obese C57/BL6 male mice (n=49) were implanted with LLC cells [1x106 cells] in the right flank or underwent sham surgery. Skeletal muscle was excised for transmission electron microscopy (TEM), histology, protein analysis, and cellular respiration 25 days following implantation or sham surgery. Cage activity and grip strength were assessed at day 0, 14, and 24. T-tests and mixed effects models were used to assess statistical differences. RESULTS: Obese LLC mice had increased tumor area (+Δ83%; p<.001) and mass (+Δ176%; p<.001), reduced survival (-Δ40%;p=.018), along with identical decreases in body weight (-Δ12%; p<.001) and skeletal muscle mass loss (-Δ21%; p<.001) compared to lean LLC mice. Preliminary TEM analysis unveils obese mice had greater evidence of mitochondrial dysfunction [auto(mito)phagic, altered cristae, contact area] (+Δ299%) regardless of LLC implantation, and identical decreases in mitochondrial content (-Δ47%) and area (-Δ53%) in obese and lean LLC mice. Cellular respiration (-Δ43%; p=.007), cage activity (-Δ66%; p<.001), and relative grip strength (-Δ56%; p<.001) were decreased in obese mice compared to lean mice but were not impacted by LLC implantation. CONCLUSIONS: Collectively, these data demonstrate obese mice had decreased survival and were not protected against skeletal muscle loss or mitochondrial perturbations associated with the LLC model of cancer cachexia. Moreover, our data highlight distinct obesity-dependent changes in muscle function and mitochondrial health which need to be explored further due their relevance in cancer-associated muscle wasting.

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