Abstract
Cancer cachexia is a result of increased protein degradation and decreased protein synthesis. The multifunctional circulating hormone ghrelin promotes synthesis and inhibits degradation of muscle protein, but its mechanism of action is not fully understood. Here, we investigated whether co-culturing C2C12 myotubes with CT26 colon carcinoma cells induces myotube atrophy, and whether acylated ghrelin (AG) and unacylated ghrelin (UnAG) had anti-atrophic effects. We found that co-culture induced myotube atrophy and increased tumor necrosis factor-alpha (TNF-α) and myostatin concentrations in the culture medium. Moreover, co-culture down-regulated myogenin and MyoD expression, inhibited the Akt signaling, up-regulated ubiquitin E3 ligase expression, and activated the calpain system and autophagy in myotubes. Both AG and UnAG inhibited these changes. Our study describes a novel in vitro model that can be employed to investigate cancer cachexia, and our findings suggest a possible use for AG and UnAG in treating cancer cachexia.
Highlights
Cancer cachexia is a multifactorial metabolic syndrome characterized by muscle wasting, systemic inflammation, and a progressive loss of muscle function [1]
After 24 hours of co-culture, myotube diameter decreased by nearly 60% in the CO group compared to the NC group (P < 0.001), and acylated ghrelin (AG)/unacylated ghrelin (UnAG) prevented this decrease (P < 0.001); no significant differences were observed between the NC, NC+AG, and NC+UnAG groups (Figure 1A and 1B)
The above results indicate that co-culture of C2C12 myotubes with CT26 cells resulted in myotube atrophy, and AG/UnAG prevented this change
Summary
Cancer cachexia is a multifactorial metabolic syndrome characterized by muscle wasting (with or without fat wasting), systemic inflammation, and a progressive loss of muscle function [1]. The ghrelin system is thought to play important roles in numerous biological functions, including appetite regulation, gastric motility, pancreatic function, metabolism, cardiovascular function, immune function, and muscle mass regulation, in both humans and animals [9,10,11]. Both AG and UnAG might inhibit muscle wasting caused by aging, thermal injury, heart failure, chronic renal failure, cancer, and chemotherapyinduced cachexia by increasing muscle protein synthesis and decreasing proteolysis [12]. In vitro and in vivo studies have shown that both AG and UnAG can reduce pro-inflammatory cytokine levels [13], suppress the transcription factors forkhead box O3A (FoxO3a) and www.impactjournals.com/oncotarget
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