The Effect Of MTMR14 Deletion On Metabolism And Atherosclerosis In Mice

Myotubularin related protein 14(MTMR14) is a novel phosphoinositide phosphatase, unlike most of protein phophatases, its most specific substrates are a series of phospholipids, not proteins, such as PI(3,5)P2, PI(3)P, etc. Recent studies have reported that MTMR14 is highly expressed in multiple tissues, such as heart, skeletal muscle, and testis. The deletion of MTMR14 caused a series of muscle disorders by disrupting calcium homeostasis. Further research demonstrated that MTMR14 might be involved in cell autophagy and proliferation, organism obesity and aging. However, the roles of MTMR14 played in metabolism, inflammation and atherosclerosis(AS) are still unclear. To explore the influences of MTMR14 deficiency on metabolism, obesity, aging and AS, MTMR14 wildtype(WT) and knockout(KO) mice were used as animal models and the experiments were performed from two part in current study.1. The influences of MTMR14 deletion on mouse metabolism and obesity were evaluated in every stage(4 weeks, 12 weeks, 18 weeks, 24 weeks and 34 weeks) of WT and KO mice. We found that aged MTMR14 KO mice even fed with the normal chow diet exhibited elevated serum total cholesterol(TC) levels, triglyceride(TG) levels and basal glucose levels, compared to their age-matched WT control. According to histological analysis, lipid accumulation was also increased in the muscle and liver of aged KO mice. Meanwhile, larger adipocytes in aged MTMR14 KO mice were also observed. The Real-time PCR results showed that several metabolism-associated genes(Glut4, adiponectin and leptin) were down-regulated in fat and muscle of aged MTMR14 KO mice. In contrast with fat and muscle, the major functions of liver are metabolites detoxification and glycerol conversion. Consequentially, the expression levels of Glut4, adiponectin and leptin are significantly exacerbated in liver. More importantly, several inflammation-associated genes(TNF-?, IL-6, IL-1? and MCP-1) were dramatically dysregulated in the metabolic tissues of aged MTMR14 KO mice relative to control mice. PI3K/AKT and ERK signaling pathways are vital for a series of chronic diseases evoked by inflammation. In this part, the dysfunction of PI3K/AKT and ERK signaling pathways also was observed. MTMR14 deficiency generally promoted the phosphorylation levels of AKT and ERK in aged MTMR14 KO mice while repressing the phosphorylation levels of ERK in muscle. All the influences of MTMR14 deletion were no significant before adult. All results indicated that PI3K/AKT and ERK signaling pathways might participate in exacerbating inflammation during adult obesity and induced chronic disease in an age-dependent manner.2. The effects of MTMR14 deficiency on AS were investigated. Four groups of different mice model with different diet were designed for experiments: Wildtype-normal chow diet(WT-NCD), knockout-normal chow diet(KO-NCD), Wildtype-high fat diet(WT-HFD) and knockout-high fat diet(KO-HFD). Compared with other groups, KO-HFD mice exhibited dramatically elevated body weight, blood glucose level, TG and TC level in a time-dependent manner. After 90 days of HFD feeding, KO-HFD mice showed the characteristics of AS with the formation of fatty streaks in the aorta. Exacerbated lipoid droplets accumulation in muscle and liver of KO-HFD mice were also observed. Next research demonstrated that the mRNA level of Glut4 and adiponectin were decreased in muscle and fat of KO-HFD mice, whereas the expressions of Leptin, Glut4 and Adiponectin were elevated in liver. In consistent with our above results, liver, as a vital organ of protein synthesis and metabolic detoxification, may play a compensative role when metabolic dysfunction impaired normal functions of muscle and fat. Meanwhile, inflammatory cytokines(TNF-α、 IL-6、 IL-1β and MCP-1) were dominantly up-regulated in muscle, liver and fat of KO-HFD mouse. Further research proved that the levels of p-AKT and p-ERK were evoked in muscle, liver and fat of KO-HFD mice. All the results indicated that MTMR14 deletion could induce AS in HFD mice and PI3K/AKT and ERK signaling pathways may participate in this process.Taken together, deletion of MTMR14 could promote metabolic disorder, inflammation and adult obesity in an age-dependent manner, and exacerbated AS in HFD mice.