Mitochondrial Health During The Development Of Cancer Cachexia In Female Mice

Abstract

Cancer-cachexia is a syndrome characterized by weight loss, anemia, and skeletal muscle wasting. Muscle mass in males and females is a strong predictor of quality of life and morbidity during cancer treatment. Mitochondrial dysfunction during cancer-cachexia has been well described in males, specifically our laboratory has found mitochondrial deteriorations to precede muscle loss in male models of cachexia. However, if these aberrations are conserved between biological sexes has yet to be investigated. PURPOSE: To investigate muscle mitochondrial health during cancer-cachexia development in female mice. METHODS: ~40 female C57BL/6J mice were implanted with ~1X106 Lewis Lung Carcinoma (LLC) cells in the right hind flank. Tumors were allowed to develop up to 4 weeks. After 3-4 weeks of tumor development, a clear dichotomy was noted in tumor burden. As such, tumor injected females were divided into high tumor (HT, tumor size > 2000 mg) and low tumor groups (LT, tumor size < 1300 mg). CON animals were age-matched to tumor mice and injected with phosphate buffered saline (PBS); therefore creating 3 experimental groups HT, LT, and CON (n=12-14/group). Mitochondrial health was measured by fluorescent histology of pMitoTimer. Results were analyzed by one-way ANOVA with Tukey’s post hoc when significant F ratios were found (p<0.05). RESULTS: Tibialis anterior, plantaris and gastrocnemius muscle masses were ~10%, ~11% and ~5% lower in HT compared to LT and CON. Analysis of pMitoTimer demonstrated no differences between groups. Circulating progesterone and estrogen were ~42% and ~60% lower in HT and LT animals compared to CON with no differences between HT and LT. CONCLUSION: LT had negligible muscle wasting when compared to HT, these differences in muscle loss did not correspond to alterations in mitochondrial health. This directly contrasts prior literature in male models of cancer-cachexia suggesting divergent mechanisms between males and females in the development of cancer-cachexia. As such, further examination of why females had a dichotomy in tumor development and subsequent wasting mechanisms are necessary in order to further understand mechanisms contributing to development of cancer-cachexia. This study was funded by the National Institutes of Health, Award: R15 AR069913/AR/NIAMS.