Cancer cachexia is a chronic wasting disorder characterized by severe loss of skeletal muscle that affects approximately 80% of cancer patients, accounting for about 20 – 30% of cancer‐related deaths. Altered rest‐activity is a hallmark of circadian disruption and is often seen in cachectic patients. Additionally, loss of skeletal muscle‐specific clock gene results in muscle atrophy similar to that seen in cancer cachexia. However, it is unknown how skeletal muscle clock gene expression is altered with the progression of cachexia. Therefore, we investigated skeletal muscle clock gene expression during cachexia. ApcMin/+mice (MIN) were harvested in the morning and evening and were analyzed for clock gene expression. There was no effect of cancer on muscle Bmal1 (p = 0.55) and Clock (p = 0.59) expression. Cry1 expression showed no significant difference compared to BL – 6 mice (p = 0.24). Per 2 (p = 0.07) and Per 3 (p = 0.02) increased expression in the evening; however there was no difference between MIN and BL – 6 (Per 2 p=0.97, Per 3 p=0.87). Rev‐ERBα showed decreased expression in BL – 6 mice in the evening (p<0.001). However, there was no difference between the morning and evening MIN mice (p=0.31). RORα showed increased expression in BL – 6 mice in the evening (p = 0.03). Additionally, BL – 6 evening was significantly higher compared to MIN evening (p=0.01). However, there was no difference between the morning and evening MIN RORα expression (p>0.99). In LLC conditioned media treated myotubes, myotube diameter was decreased (p<0.001), and Bmal1 expression was decreased after 4 days in LLC conditioned media. In conclusion, the data suggest circadian clock expression is altered in a cachectic environment. Addition research is needed to understand the influence of these changes on the progression of cancer cachexia. Understanding the role of muscle‐specific circadian clock could lead to potential therapeutic interventions to attenuate cancer cachexia.

Omega‐3 fatty acids are essential fats that the body cannot produce on its own and play a very integral role in the body in regard to inflammation and hormone production. Glucocorticoids are hormones that are also effective in inflammation reduction and suppressing the immune system; however, often have many detrimental side effects such as adipose accumulation, muscle atrophy and metabolic dysfunction. The purpose of this research experiment was to examine the effects dexamethasone treatment in combination with diets high in either omega‐3 fatty acids or omega‐6 fatty acids on markers of lipid metabolism in the liver. For a span of 4 weeks, two groups of mice were placed on a diet consisting of 45% fat containing either high omega‐3 or omega‐6 fatty acids. On the fifth week mice were randomized to two groups per diet and received either PBS placebo or Dexamethasone (Dex) injections daily. We hypothesized that Dex treatment would induce liver lipid accumulation and an omega‐3 rich diet would prevent this. At the completion of the 5 weeks, tissue was harvested and liver triglycerides were measured. There was a main effect of omega‐3 diet to have lower liver triglyceride levels (p=0.01). Fasn, Crat, Hsl, Cd36, and Fabp mRNA levels were measured in liver tissue. The resulted show that CratmRNA (p=.0153) and HslmRNA (p=.0417) was increased with omega‐3 rich diet, but there was no effect of Dex treatment. The Cd36 (p=.0495) and Fabp(p=.0229) mRNA increased in omega‐6 rich diets treated with Dex and omega‐3 high fat diet attenuated this increase. It can be concluded that one week of Dexamethasone treatment altered liver lipid signaling primarily by increasing lipid import and transport regulators, and omega‐3 high fat diet was able to prevent this increase. Additionally, omega‐3 high fat diet increase markers of lipid metabolism that were unaltered with one week of dex. These data suggest that omega‐3 fatty acids may help prevent the detrimental side effects of glucocorticoid treatment.

Glucocorticoids (GCs) are some of the most widely prescribed therapies for treating numerous inflammatory diseases and multiple cancer types. With chronic use, GCs’ therapeutic benefits are concurrent with deleterious metabolic side effects, which worsen when combined with a high-fat diet (HFD). One characteristic of the common Western HFD is the presence of high omega-6 polyunsaturated fatty acids (PUFAs) and a deficiency in omega-3 PUFAs. The aim of this experiment was to determine whether fat composition resulting from HFD affects glucocorticoid-induced alterations in lipid-handling by the liver and skeletal muscle. 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 dexamethasone (3 mg/kg/day) or sterile PBS for 1 week while continuing diets. The n-3 HFD diet attenuated adipose and hepatic fatty accumulation and prevented GC-induced increases in liver lipid metabolism markers Cd36 and Fabp. N-3 HFD had little effect on markers of lipid metabolism in oxidative and glycolytic skeletal muscle and was unable to attenuate GC-induced gene expression in the muscle. The present study’s result demonstrated that the change of fat composition in HFD could beneficially alter the fatty acid accumulation and associated lipid metabolism markers in mice treated with dexamethasone.