Differential Induction Of Regulators Of Protein Turnover During C26-induced Cancer Cachexia Between Biological Sexes

Cancer cachexia (CC) is a wasting syndrome characterized by an ongoing loss of muscle tissue that negatively affects quality of life and survival rate for cancer patients. Preclinical CC studies have focused on potential therapeutic targets to ameliorate cachectic phenotypes. A recent study revealed Redd1 as a key regulator of CC in rodent models. However, it is unknown if CC affects Redd1 differently between biological sexes in different muscle fiber types. PURPOSE: To assess the role of Redd1 in different muscle types between sexes. METHODS: 64 male and 59 female BALB/c mice were injected subcutaneously to the hind flanks with C26 colon carcinoma cells or PBS at 8-wk old and tumors were allowed to develop for 10, 15, 20, and 25 days. Muscle tissues (Tibialis anterior; TA, Gastrocnemius; GC, and Soleus) were collected at designated time points. All tissues were prepared for qRT-PCR to determine mRNA contents for protein turnover. A one-way ANOVA was utilized within each sex as the global analysis with α = 0.05. RESULTS: In male TA, Redd1, Atrogin, and MuRF were greater in 25d than other groups (2.2-8.4 fold; p < 0.01). In female TA, Redd1 was 2.2-3.5 fold greater in 25d than PBS and 15d (p < 0.05). Deptor was 2.7 fold greater in 25d than PBS (P < 0.05). Atrogin was greater in 25d than PBS, 10d, 20d, and 25d (1.6-2.4 fold; p < 0.05). MuRF was greater in 25d than PBS, 10d, and 20d (4.2-6.8 fold; p < 0.05). In male GC, Redd1, Atrogin, and MuRF were greater in 25d than other groups. (2.2-8.3 fold; p < 0.01). In female GC, Redd1 was greater in 20d than PBS and 10d (2.7-6 fold; p < 0.05). Atrogin was 3.6 fold greater in 20d than 15d (p < 0.05). In male soleus, Redd1 was greater in 25d than PBS, 10d and 15d (1.7-3.4 fold; p < 0.01). Deptor was ~1.3 fold lower in 15d than PBS and 25d (~1.3 fold; p < 0.05). Atrogin and MuRF were greater in 25d than other groups (1.3-2 fold; p < 0.01). In female soleus, Redd1, Atrogin, and MuRF were greater in 25d than other groups (2-5.7 fold; p < 0.01) Deptor was 1.5 fold lower in 15d than 25d (p < 0.05). CONCLUSION: mRNA targets for atrogenes (Atrogin, MuRF), and the anabolic repressor (Redd1) were upregulated as tumors develop. Interestingly, more robust upregulation of Redd1 than atrogenes was observed in different muscle types in both sexes, suggesting it may serve as a reliable mRNA marker for C26-induced CC. Supported by NIH Grant R01 AR075794-02.