The Role of Skeletal Muscle Intrinsic Clock in the Development and Progression of Cancer Cachexia

Abstract

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.