Introduction Many forms of cancer are associated with loss of lean body mass, a significant indicator of increased mortality. This effect is commonly attributed to decreased protein synthesis and stimulation of proteolytic pathways within the skeletal muscle due to metabolic disturbances from the tumor burden. The branched chain amino acid (BCAA) leucine has been shown to improve protein synthesis, insulin signaling, and mitochondrial biogenesis, key signaling pathways influenced by tumor signaling. Purpose Our study aimed to elucidate the effects of leucine supplementation on mitochondrial biogenesis, within the Lewis Lung Carcinoma (LLC) implantation model. We hypothesized that LLC implantation will impair mitochondrial biogenesis and protein synthesis leading to a loss of muscle mass, with leucine attenuating these effects. Methods Twenty male C57BL/6 mice were divided into four equal groups (n=5) of equivalent body weight: Chow, leucine (Leu), LLC, LLC+Leu. At the age of 9–10 weeks, mice received a subcutaneous injection of 1×106 LLC cells or phosphate buffered saline (PBS). Leu groups were then switched to diet supplemented with 5% leucine (w/w). Upon euthanasia, muscle and tumors were weighed and collected. Measures of protein synthesis, mitochondrial biogenesis, and inflammation in the gastrocnemius muscle were assessed via western blot analysis. Results While body mass was not different between groups, gastrocnemius mass was decreased in the LLC+Leu group relative to the LLC group (p=0.040). Protein synthesis, quantified through the SUnSET technique, was decreased in LLC mice (p=0.001). Phosphorylation of STAT3, an indicator of inflammation was decreased in the Leu group relative to the control (p=0.019), but did not significantly attenuate the inflammatory effect of LLC implantation (p=0.619). Peroxisome proliferator‐activated receptor Gamma Co‐activator 1‐α (PGC‐1α), a marker of mitochondrial biogenesis, was increased in LLC+Leu relative to LLC (p=0.001). Finally, LLC implantation decreased mitochondrial content as measured by Cytochrome C (p=0.015), mitochondrial complexes III (p=0.006) and V (p=0.041). Conclusion Within our study, leucine supplementation was unable to preserve protein synthesis or mitochondrial content associated with LLC implantation. However, Leucine supplementation was able to increase mitochondrial biogenesis signaling. Support or Funding Information University of Memphis School of Health Studies Faculty Grant This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Time-restricted feeding (TRF) is becoming a popular way of eating in physically active populations, despite a lack of research on metabolic and performance outcomes as they relate to the timing of food consumption in relation to the time of exercise. The purpose of this study was to determine if the timing of feeding/fasting after exercise training differently affects muscle metabolic flexibility and response to an acute bout of exercise. Male C57BL/6 mice were randomized to one of three groups for 8 weeks. The control had ad libitum access to food before and after exercise training. TRF-immediate had immediate access to food for 6 h following exercise training and the TRF-delayed group had access to food 5-h post exercise for 6 h. The timing of fasting did not impact performance in a run to fatigue despite TRF groups having lower hindlimb muscle mass. TRF-delayed had lower levels of muscle HSL mRNA expression and lower levels of PGC-1α expression but displayed no changes in electron transport chain enzymes. These results suggest that in young populations consuming a healthy diet and exercising, the timing of fasting may not substantially impact metabolic flexibility and running performance.
Treatment with synthetic glucocorticoids induces muscle atrophy and are commonly used in the treatment of a variety of inflammatory and autoimmune diseases. Omega‐3 (n‐3) polyunsaturated fatty acids elicit beneficial effects in several muscle atrophy conditions. Therefore, the purpose of this study was to determine if a high‐fat diet rich in n‐3 is protective of glucocorticoid‐induced protein degradation. Male wild type C57BL/6 mice were randomized into two groups: n‐6 (45% fat 177.5 g lard) and n‐3 (45% fat 177.5 g Menhaden oil). After 4 weeks on their diets, groups were divided to receive either daily injections of 3 mg/kg/day dexamethasone (Dex) or sterile phosphate buffered saline, for 1 week while continuing diets. At sacrifice the gastrocnemius muscle was weighed and dissected into red and white portions before being snap frozen and processed for RNA extraction and protein extraction. Dex reduced gastrocnemius weight by 12% independently of diet. Protein degradation signaling in the white gastrocnemius was altered by Dex with increased atrogin‐1 expression (p=0.004) without a change in muscle RING finger 1 (MuRF‐1) expression (p=0.15). There was a large effect of Dex to decreased phosphorylation of forkhead box transcription factor O3a (FOXO3a) (Cohen’s d=1.42), increased phosphorylation of glycogen synthase kinase 3β (GSK‐3β) (Cohen’s d=1.42). However, the negative effects of dexamethasone were not attenuated by an n‐3 high‐fat diet. There was no effect of Dex or diet on phosphorylation of FOXO3a (p=0.17) or GSK3β (p=0.60) in red gastrocnemius muscle. These data support the detrimental effects of dexamethasone on muscle atrophy and report no benefit of an n‐3 high‐fat diet. Support or Funding Information Funding provided by University of Memphis School of Health Studies
Fat is an essential source of energy and is important for human growth and development. A high fat diet, however, leads to pathological obesity and associated comorbidities, such as reduced lifespan and muscle strength in both humans and model organisms. In this study we analyzed the effects of four dietary fats on lifespan and overall health using a Drosophila model system, which shares the mechanisms of energy processing, storage, and utilization with humans. One day old wild type male Drosophila were collected and placed on a control diet or high fat diets containing 5%, 10% or 15% of coconut oil (medium chain‐saturated fat), vegetable oil, olive oil, or flax seed oil (all three contain unsaturated fats). Lifespan was determined for 100 flies on each diet. Skeletal muscle performance was evaluated by climbing and flying assays. Among all the groups, flies on a control diet had the greatest survival with a median lifespan of 30.5 days, while flies on a 5% coconut oil diet had the second longest survival time, yielding a median lifespan of 13 days. For all other diets, the median lifespan was 2 days. Flies on the control diet also performed significantly better (p<0.05) in the flying and climbing assays relative to flies on high fat diets. Flies on a 5% coconut oil diet had a significantly higher (p<0.05) muscle strength based on the flying assay compared to flies maintained on 5% diets with unsaturated fats. Interestingly, intestinal permeability measured using the Smurf assay revealed no difference between flies maintained on a control diet, 5% coconut oil diet, and 5% vegetable oil diet, suggesting that the adverse health effects of a high fat diet did not result from the compromised function of the intestine. Taken together, these data indicate that plant based medium chain saturated fats preserved longevity and muscle function better than plant‐based fats containing high amounts of polyunsaturated fatty acids. Support or Funding Information Funding Source: University of Memphis SHS Faculty Grant
Intermittent fasting refers to a period of unregulated caloric consumption paired with a period of complete, or heavily restricted, caloric consumption. One version of this involves splitting the day into a consumption period and a restricted period, known as time‐restricted feeding (TRF). TRF is shown to improve metabolic health and positively affect mitochondria, independent of weight loss. Aerobic exercise is also shown to improve these parameters; however, the combination of intermittent fasting and aerobic exercise in a healthy system has not been examined. The purpose of this study was to examine the effects of the feeding window time in relation to exercise on body weight, body fat percentage, lean mass, and run to exhaustion. Healthy, young mice were placed in one of three groups: ad libitum control group (CON), 18‐hour fasting with a 6‐hour feeding starting immediately post exercise (IM), and 18‐hour fasting with a 6 hour feeding starting 5 hours post exercise (DG). The mice ran 5 days a week, 1 hour a day, for a total of 8 weeks at the beginning of the dark cycle. A run to exhaustion (RTE) was conducted at week 0 and week 8 of the study. Mice were weighed twice weekly and underwent an MRI once a week. Data are presented as mean ± SD. A repeated measures two‐way ANOVA was used to compare groups across time. Significance was set a p< 0.05. There were no significant differences between RTE times at week 0 (p= 0.52). There was a main effect of training across all groups in RTE (p=0.04) with a 14±43% increase in RTE in the CON, 13±33% increase in IM, and 55±86% increase in DG. There was a significant increase in body fat in the DG compared to CON at week 2 (CON 7.1±4.5% DG 13.4±2.3%, p=0.002), week 3 (CON 7.2±4.8% DG 11.6±2.6, p=0.02), and week 4 (CON 7.0±4.5% DG 11.6±1.9%, p=0.006); however, there was no difference between groups at week 8. There was a significant effect of time on body weight and lean mass, demonstrating normal growth (p<0.0001). TRF did not have a significant effect (p=0.24) on body weight, however there was a significant decrease in lean mass in TRF groups at week 8 (CON 24.7±2.2g, IM 22.8±2.1g, DG 22.7±1.8g, p=0.03). Although there was a small decrease in lean mass, TRF did not lead to a change in performance as measured by RTE and timing of fasting did not impact either RTE or body composition. This suggests that performance may not be substantially impacted in individuals using TRF, regardless of the timing of the feeding window. Support or Funding Information Funded by the University of Memphis School of Health Studies
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