Impact of prior alcohol use on the subsequent development of cancer cachexia in male and female mice.

BACKGROUND: Alcohol is a carcinogen and its intake prior to developing cancer and throughout its duration exacerbates cancer cachexia in rodent models. However, the effects on cancer cachexia of stopping alcohol prior to tumor establishment are unknown. METHODS: Male and female mice consumed either a nonalcohol control liquid diet (CON) or a 20% ethanol (kcal/day) liquid diet (EtOH) for 6 weeks. All mice then consumed a control diet and mice in the cancer groups were inoculated with C26 colon cancer cells. Gastrocnemius muscles were collected and analyzed after ~2 weeks. RESULTS: Skeletal muscle weight and male epididymal and female perigonadal fat mass were reduced more by the combination of cancer and prior EtOH than either exposure alone in both males and females. In males, protein synthesis was reduced by 30% following alcohol exposure, while no reductions were observed in female mice. AMPK Thr172 phosphorylation was increased in both male and female EtOH-Cancer groups, while Akt Thr308 phosphorylation was reduced only among males in EtOH-Cancer mice. Substrates in the mTORC1 pathway were reduced by cancer in both males and females, but prior alcohol intake only reduced phosphorylation of 4E-BP1 Ser65 and rpS6 Ser240/244 to a greater extent in male, but not female, mice. Autophagic and proteasomal signaling were largely unaffected by prior alcohol intake in cancer mice, despite a greater increase in Murf1 mRNA in both sexes. CONCLUSIONS: Prior alcohol consumption accelerates or worsens the onset of certain aspects of cancer cachexia in a sex-dependent manner, with males being more sensitive to these exposures, even with abstinence from alcohol prior to tumor initiation.

Mealtime alcohol consumption suppresses skeletal muscle mTORC1 signaling in female mice.

OBJECTIVE: To determine whether alcohol consumed within the meal influences the feeding induced increase in mTORC1 signaling. METHODS: Alcohol provided in the liquid diet was consumed by alcohol naïve, fasted, C57BL/6Hsd female mice and gastrocnemius was collected 1hr after the refeeding. Subsequent experiments determined the extent to which changes in mTORC1 signaling persisted across the day. RESULTS: Compared with control mice, protein synthesis, mTORC1 (Ser2448), 4EBP1 (Ser65), S6K1 (Thr389), rpS6 (Ser240/244), Akt (Thr308), and ULK1 (Ser757) were lower in EtOH. Similar suppressive patterns were observed in the hours following consumption of alcohol containing food throughout the dark cycle. Higher peak blood alcohol concentrations induced by intraperitoneal injection of alcohol extended the time and magnitude of mTORC1 pathway suppression. CONCLUSION: Alcohol administered as part of the meal results in lower skeletal muscle mTORC1 signaling while subsequent models show that alcohol may influence this pathway across the day.