Chronic alcohol consumption has been commonly reported to induce skeletal muscle loss, however data observing the impact of diet composition and alcohol on muscle mass, particularly between sexes, remains scarce. PURPOSE To observe how differences in dietary composition influence the effects of alcohol on skeletal muscle mass in male and female mice. METHODS C57BL/6 mice (n=72; m=36; f=36) aged 12‐weeks‐old were acclimated to a liquid diet for one‐week prior to randomization into either a control (CON: 35% FAT, 47% CHO, 18% PRO) or one of three alcohol (EtOH) treatment groups of differing dietary composition: high‐fat (HF: 35% FAT, 15% CHO, 18% PRO), low‐fat (LF: 12% FAT, 38% CHO, 18% PRO) or high‐protein (PRO: 12% FAT, 31% CHO, 25% PRO). Alcohol was incorporated into the diet and increased over time to a maximum intake of 32% kcal of the diet. Daily consumption of EtOH was assessed relative to body weight. After 7 weeks, the gastrocnemius (GAS) and quadriceps (QUAD) muscles were excised, along with the heart and spleen, which were weighed and expressed relative to body weight. Blood was taken at sacrifice for blood EtOH concentration (BAC); however, feeding status and therefore alcohol intake, was ad libitum up until the time of sample collection. Data were analyzed via 2‐way ANOVA for variables across time, and unpaired t‐tests were used to detect differences between diets and control groups, and between sexes within diets. RESULTS No significant interactions nor main effects were observed for EtOH consumption between diets within each sex. A significant main effect of sex was observed for EtOH consumption within all diets, where females consumed more EtOH than males (HF: F=71.79, 5.18 ± 0.61 g/kg; LF: F=53.55, 4.37 ± 0.60 g/kg; PRO: F=38.45, 4.75 ± 0.77 g/kg; p’s <0.0001). No main effect of diet was observed for either sex for BAC (p≥0.98) at sacrifice. Female GAS was significantly reduced in HF and LF compared to CON (−8.31 ± 3.74%, p=0.043; −10.53 ± 3.74%, p=0.01 respectively), while no changes were noted for Male GAS. Female QUAD was significantly reduced in HF and LF compared to CON (−10.81 ± 4.52%, p=0.03; −13.63 ± 3.58%, p<0.01 respectively), while no changes were observed for male QUAD. Female heart weights were significantly reduced in HF and LF compared to CON (−12.35 ± 4.33%, p=0.01; −11.34 ± 3.88%, p<0.01 respectively), while an increase in LF was observed in males (9.89 ± 2.55%, p<0.01). Furthermore, female spleen weight was significantly reduced in LF and PRO (−18.39 ± 7.22%, p=0.02; −19.06 ± 6.45%, p=0.01 respectively), while no differences were noted for males. CONCLUSIONS Despite consuming equivalent amounts of EtOH between diets within each sex, females in HF and LF diets experienced significant muscle atrophy compared to CON, while no reductions were observed in PRO. However, this alcohol feeding protocol did not induce significant muscle atrophy in male mice. A possible explanation for these sex differences is that over time, female mice consumed significantly more EtOH relative to body weig...
Cancer cachexia results in a loss of skeletal muscle mass, leading to increased morbidity and mortality. Similarly, chronic alcohol consumption leads to skeletal muscle loss and dysfunction. It is unknown, whether prior alcohol intake or its continued use after cancer establishment, exacerbates cancer cachexia. Anabolic pathways are central to the maintenance of muscle mass and are notoriously decreased by alcohol intake. Among these pathways, the mTORC1 pathway and subsequent rates of protein synthesis are of central importance to the maintenance of muscle health. Purpose To determine if prior or concurrent alcohol consumption worsens skeletal muscle anabolic signaling (i.e. puromycin and mTOR pathway) during cancer cachexia. Methods Male CD2F1 mice (n=42), 12‐weeks old, were randomized into 6 groups (n=6‐8/gr): control (CON), control‐cancer (CON‐C), prior EtOH (PRIOR), prior EtOH‐cancer (PRIOR‐C), continuous EtOH (EtOH), and continuous EtOH w/cancer (EtOH‐C). Mice were acclimated to a control liquid diet, after which the EtOH groups transitioned to the Lieber DeCarli EtOH diet at 20% kcal EtOH for 6 weeks. At week 7, PRIOR mice weaned off EtOH and remained on the control diet until sacrifice. Also at week 7, cancer mice were injected subcutaneously on the right flank with C26 colon carcinoma cells (1x106 cells) and consumed their assigned diet for 14 days while tumors developed. After a 4‐hour fast, puromycin was injected and 30 minutes later the gastrocnemius (GAS) was excised. GAS protein was isolated and Western Blots performed. Data were analyzed via 1‐way ANOVA with post hoc testing when appropriate. Data are presented relative to CON (set to 100%) as mean ± SE, with protein expression normalized either to ponceau staining or total levels of the given protein. Results Body weight at sacrifice was lower in the PRIOR‐C and EtOH‐C (p<0.05) indicating an alcohol effect. Tumor weight and tibia length were not different between groups. GAS weight was reduced by cancer in all groups, and most notably in PRIOR‐C and EtOH‐C mice (p<0.001). Protein synthesis, assessed by puromycin, decreased in all cancer groups, with a ~70% reduction in PRIOR‐C and ~82% reduction in EtOH‐C relative to CON. Similarly, phosphorylation of S6K1 Thr389, rpS6 Ser240/244 and Ser235/236 was significantly reduced in PRIOR‐C and EtOH‐C relative to CON (p<0.05), indicating a greater reduction in these markers of mTORC1 activity with alcohol intake. Surprisingly, no differences in 4E‐BP1 Ser65, mTOR Ser2448, or mTOR Ser2481 were observed across groups. PRAS40 Thr246 was increased by cancer alone as well as in EtOH‐C mice (35% vs. CON) (p<0.05). Increases in eEF2 Thr56 were also detected in PRIOR‐C (50%) and EtOH‐C (83%) (p<0.05), possibly indicating impaired peptide chain elongation. No changes were noted in markers of protein breakdown including ubiquitinated proteins, and autophagic proteins ULK1 Ser757 and LC3B‐II/I. Conclusions The intake of alcohol both prior to, and during tumor development lead to greater decreases in GAS weight, protei...
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